bluuebunny/crossref_metadata_2025 huggingface dataset:
Atypical Cat Scratch Disease With Splenic Lesion Mimicking Kawasaki Disease in a Healthy 5-Year-old Girl
Authors: Ma Minjae , Aoki Yoshihiro , Kitazawa Katsuhiko
Published: November 2023

Background:

Atypical cat scratch disease (CSD) and Kawasaki disease (KD) are differential diagnoses of pediatric febrile illnesses. Diagnosing atypical CSD can be challenging because of its wide range of symptoms. However, its similarity to KD has rarely been addressed.

Methods:

We present the case of a 5-year-old girl with atypical CSD and splenic lesions who fulfilled the diagnostic criteria for KD. We also conducted a literature review of previous cases in which CSD was suspected alongside KD and detailed the diagnosis and treatment processes.

Results:

A previously healthy 5-year-old girl with prolonged fever and symptoms resembling those of KD was admitted to our hospital. There was no evidence of an abnormal coronary artery, and her condition did not improve after the initial treatment for KD and bacterial infection. A history of contact with cats and multiple granulomatous lesions in the spleen on abdominal ultrasonography led to a clinical diagnosis of atypical CSD. Trimethoprim-sulfamethoxazole treatment resulted in symptom resolution. Elevated serum Bartonella henselae IgG and IgM antibodies confirmed the diagnosis of CSD. In this case, we avoided second-line treatment for KD with an alternative CSD diagnosis. Additionally, we identified 4 documented cases of CSD presenting with KD-like features in the literature. Intravenous immunoglobulin was ineffective in all cases, including the present case.

Conclusions:

In cases of atypical CSD where KD is suspected, actively seeking organ-specific symptoms may facilitate an early clinical diagnosis of CSD. Adopting this approach could yield multiple advantages, including reduced invasiveness for the patient and decreased healthcare-related expenditures.
Real-world clinical efficacy of nemolizumab in Japanese patients with atopic dermatitis
Authors: Watanabe Yoshinori , Ishiuji Yozo , Ogawa-Tominaga Minako , Katsuta Michie , Asahina Akihiko
Published: November 2023

Nemolizumab was approved in Japan in August 2022 to treat patients with atopic dermatitis (AD). The study objective was to evaluate its effectiveness in controlling AD symptoms in the real world postmarketing. Eleven Japanese patients with AD treated with nemolizumab were assessed at 12 weeks for clinical manifestations, AD scores Visual Analog Scale and Eczema Area and Severity Index, and serum biomarkers. Visual Analog Scale and Eczema Area and Severity Index scores were significantly decreased by 80% and 66.4%, showing nemolizumab improved both itch and skin lesions. However, several serum AD biomarkers did not change during treatment with nemolizumab.
Oxygen Targets After Cardiac Arrest: A Meta-analysis of Randomized Controlled Trials
Authors: Singh Sahib , Rout Amit , Chaudhary Rahul , Garg Aakash , Tantry Udaya S. , Gurbel Paul A.
Published: November 2023

Background:

Optimal oxygen saturation target in patients resuscitated after cardiac arrest is unknown. Previous randomized controlled trials (RCTs) comparing restrictive oxygen therapy with liberal therapy have shown conflicting results.

Study Question:

We performed a meta-analysis of available RCTs to consolidate the contrasting findings regarding the oxygen targets after cardiac arrest.

Data Sources:

We searched electronic databases for RCTs comparing restrictive versus liberal oxygen targets in patients resuscitated after cardiac arrest.

Study Design:

End points of interest were mortality, unfavorable neurological outcomes, and rearrests. Random-effects meta-analysis was performed to estimate the risk ratio (RR) with a 95% confidence interval (CI).

Results:

Eight RCTs with 1641 patients (restrictive n = 833, liberal n = 808) were included in the analysis. The oxygen targets were defined by either saturation, partial pressure (PaO2), or supplementation rates. The mean age and male percentage were 63 years and 80%, respectively. There was no significant difference observed in the 2 groups for overall mortality (RR = 0.91, 95% CI = 0.75–1.10, P = 0.33), unfavorable neurological outcomes (RR = 0.93, 95% CI = 0.74–1.18, P = 0.56), and rearrests (RR = 0.67, 95% CI = 0.22–1.98, P = 0.47).

Conclusions:

Overall, this meta-analysis shows no significant difference in mortality, unfavorable neurological outcomes, and rearrests when using restrictive or liberal oxygen targets in patients after cardiac arrest. The limitations in the newer trials should be kept in mind while interpreting the overall results.
Vaccine Immunity in Children After Hematologic Cancer Treatment: A Retrospective Single-center Study
Authors: Cetin Melissa , Gumy-Pause Fabienne , Gualtieri Renato , Posfay-Barbe Klara M. , Blanchard-Rohner Geraldine
Published: November 2023

Background:

Children lose their vaccine-induced protection and are particularly vulnerable to vaccine-preventable diseases after chemotherapy. However, revaccination guidelines are heterogeneous, and there is often a lack of revaccination post-treatment.

Aims:

We conducted a retrospective study of children with hematologic cancer to evaluate vaccine immunity before and after the end of treatment and to determine whether the current institutional revaccination program based on vaccine serology results was followed and effective.

Materials and Methods:

Data of all children treated by chemotherapy between April 2015 and July 2021 were extracted from hospital medical records for analysis. Serum antibody levels and time of vaccination were evaluated for diphtheria, tetanus, Streptococcus pneumoniae, Haemophilus influenzae type b (Hib), measles, varicella, and hepatitis B.

Results:

We included 31 patients (median age, 9 years). At cancer diagnosis, 90% of children were protected against tetanus, diphtheria, and measles; 65% to 67% were protected against pneumococcus and varicella; and 25% against hepatitis B. At the end of chemotherapy, 67% to 71% of patients were protected against tetanus, varicella, and measles; 40% remained protected against hepatitis B; and 27% to 33% against pneumococcus and diphtheria. Patients were revaccinated at various times after the end of treatment but not systematically. During the first-year post-treatment, 20% to 25% of children remained unprotected against pneumococcus, measles, and hepatitis B, one third against diphtheria, but all were protected against tetanus and varicella.

Conclusions:

An effective individualized vaccination program post-cancer based on serology results should be accompanied by an appropriate serology tracking method and follow-up to assess if booster doses are necessary. Our study supports vaccinating all children with a dose of the 13-valent pneumococcal conjugate at cancer diagnosis and at 3 months post-treatment with the combined diphtheria-tetanus-acellular pertussis/poliomyelitis vaccine/hepatitis B virus plus or minus Hib and 13-valent pneumococcal conjugate and meningococcal vaccine, including measles/mumps/rubella-varicella zoster virus vaccine if good immune reconstitution is present.
Assessment of The Utility of The Sarcoma DNA Methylation Classifier In Surgical Pathology
Authors: Miettinen Markku , Abdullaev Zied , Turakulov Rust , Quezado Martha , Luiña Contreras Alejandro , Curcio Christian A. , Rys Janusz , Chlopek Malgorzata , Lasota Jerzy , Aldape Kenneth D.
Published: November 2023

Diagnostic classification of soft tissue tumors is based on histology, immunohistochemistry, genetic findings, and radiologic and clinical correlations. Recently, a sarcoma DNA methylation classifier was developed, covering 62 soft tissue and bone tumor entities. The classifier is based on large-scale analysis of methylation sites across the genome. It includes DNA copy number analysis and determines O6 methylguanine DNA methyl-transferase methylation status. In this study, we evaluated 619 well-studied soft tissue and bone tumors with the sarcoma classifier. Problem cases and typical examples of different entities were included. The classifier had high sensitivity and specificity for fusion sarcomas: Ewing, synovial, CIC-rearranged, and BCOR-rearranged. It also performed well for leiomyosarcoma, malignant peripheral nerve sheath tumors (MPNST), and malignant vascular tumors. There was low sensitivity for diagnoses of desmoid fibromatosis, neurofibroma, and schwannoma. Low specificity of matches was observed for angiomatoid fibrous histiocytoma, inflammatory myofibroblastic tumor, Langerhans histiocytosis, schwannoma, undifferentiated sarcoma, and well-differentiated/dedifferentiated liposarcoma. Diagnosis of lipomatous tumors was greatly assisted by the detection of MDM2 amplification and RB1 loss in the copy plot. The classifier helped to establish diagnoses for KIT-negative gastrointestinal stromal tumors, MPNSTs with unusual immunophenotypes, and undifferentiated melanomas. O6 methylguanine DNA methyl-transferase methylation was infrequent and most common in melanomas (35%), MPNSTs (11%), and undifferentiated sarcomas (11%). The Sarcoma Methylation Classifier will likely evolve with the addition of new entities and refinement of the present methylation classes. The classifier may also help to define new entities and give new insight into the interrelationships of sarcomas.
Synchronous Endometrial and Ovarian Carcinomas: Pathologic and Molecular Analysis Highlights the Monoclonal Origin of the Lesions
Authors: Guerriero Angela , Moro Margherita , Angerilli Valentina , Munari Giada , Santoro Luisa , Alessandrini Lara , Favero Lara , Tasca Giulia , Fassan Matteo , Dei Tos Angelo Paolo
Published: November 2023

The diagnosis of synchronous carcinomas, involving both the endometrium and ovaries, is not a rare finding in gynecologic pathology and represents a challenge with implications on tumor staging and therapeutic decision-making. A mono-institutional series of 11 metastatic and 6 paired synchronous endometrial and ovarian carcinomas were reviewed by 2 expert pathologists based on previously published histopathologic criteria. The series was investigated for DNA mismatch repair proteins, p53, and POLE status and was subject to DNA-based next-generation sequencing targeting 67 cancer-related genes. Out of 17 pairs, 16 featured the same histotype (10 endometrioid, 4 serous high-grade, and 2 clear cells). By using WHO 2020 criteria, 11 couples of tumors were confirmed as metastatic and 6 couples were confirmed as independent. Based on next-generation sequencing analysis, 16 of 17 cases (11 metastatic and 5 independent) of our series showed evidence of a clonal relationship between endometrial and ovarian carcinomas. In metastatic cases, the adverse outcome was associated with nonendometrioid/high-grade endometrioid histotype and with the p53-abnormal molecular subtype. Four cases originally fulfilling clinicopathological criteria of independent endometrial and ovarian carcinomas were clonally related, low-grade endometrioid histotype and POLE-mut, mismatch repair deficient, and no specific molecular profile molecular subtypes; no adverse event was recorded in this group. In summary, the molecular characterization of synchronous gynecologic carcinomas confirms their clonal origin in most cases. However, the results of our study point out that the clinical behavior of these tumors seems to be determined by the presence of high-risk WHO 2020 histologic criteria and molecular features (i.e. p53-abnormal), rather than the monoclonal origin.
Dedifferentiated Leiomyosarcoma-morphology, Immunohistochemistry, and Molecular Findings of a Case and Review of Literature
Authors: Kousar Aisha , Wald Abigail I. , Heayn Michelle , Cardillo Nicholas D. , Elishaev Esther , Bhargava Rohit
Published: November 2023

We present a case of uterine dedifferentiated leiomyosarcoma in a 42-yr-old woman who presented with severe abdominal pain and vaginal bleeding. The mass measured 10.5 cm. The “differentiated” tumor component ranged from leiomyoma-like areas to smooth muscle tumor of uncertain malignant potential to frank leiomyosarcoma. The undifferentiated tumor component showed extreme hypercellularity, intermediate to large polygonal cells, with significant cytologic atypia and numerous mitotic figures (67 mitotic figures per 10 high-power fields). This undifferentiated component imperceptibly blended into more recognizable smooth muscle areas. In contrast to the differentiated component, the undifferentiated component lacked staining for smooth muscle markers. Targeted next-generation sequencing revealed TP53, NF1, and NOTCH2 mutations in both differentiated and undifferentiated components. In addition, the undifferentiated tumor component also harbored multiple additional chromosomal abnormalities including gains in 1q, 22q, and copy number losses in 3p, 9p, and 11q. The undifferentiated tumor component was also identified in an adhesion involving the small bowel and omentum at complete staging. The patient was subsequently treated with 6 cycles of adriamycin chemotherapy. Computerized tomography scan after 3 cycles showed no residual disease. Published literature regarding dedifferentiated leiomyosarcoma is reviewed.
Uterine Neurotrophic Tyrosine Receptor Kinase Rearranged Spindle Cell Neoplasms: Three Cases of an Emerging Entity
Authors: Grant Lucy , Boyle William , Williams Sarah , Pascoe Jennifer , Ganesan Raji
Published: November 2023

Uterine sarcomas are rare; most are either smooth muscle or endometrial stromal in origin. Recent molecular advances have identified several, genetically defined entities with specific morphologic, clinicopathological associations, and therapeutic options. We report 3 cases of uterine neurotrophic tyrosine receptor kinase (NTRK)-rearranged spindle cell neoplasms,” currently classified as “emerging entities” in the WHO Classification of Female Genital Tract Tumors, 2020, Fifth Edition. The affected patients were 32, 34, and 42 years of age. Two patients presented with vaginal bleeding; the third presented with a cervical mass found incidentally during laparoscopy for an ectopic gestation. All 3 tumors were polypoid masses that distorted the cervix. Microscopically, they comprised cellular, fascicular, and storiform, plump spindle cells, with occasional rounded cells, and frequent mitoses (4–48/10 high power fields) in a myxoid stroma. All 3 cases showed entrapment of benign cervical glands. Inflammatory cell infiltrates, including plasma cells, were noted in all 3 tumors. One case had tumor cell necrosis, osteoid-like material, and osteoclast-like giant cells and showed lymphovascular invasion. Immunohistochemically, our cases showed patchy S100 (2/3) and CD34 (3/3) positivity. CD10 was positive in 2/3 cases. 3/3 cases showed pan-tropomyosin receptor kinase positivity (cytoplasmic). The NTRK-translocations demonstrated were: NTRK1::TMP3, NTRK1::TPR, and NTRK3::SPECC1L. Two of the patients had extensive disease and underwent chemotherapy. Larotrectinib was approved for one patient who demonstrated a striking reduction in tumor volume upon initiation of this treatment.
Metastatic Hepatocellular Carcinoma Represents an Important but Rare Pitfall in the Diagnostic Evaluation of ER Negative Ovarian Malignancy: A Case Report
Authors: Viki Mthulisi , Morrow Rebecca
Published: November 2023

Metastatic hepatocellular carcinoma (HCC) to the ovary is a rare and challenging histopathological diagnosis in the absence of the relevant clinical history. The differential diagnoses of a hepatoid tumor in the ovary are extensive, and correct diagnosis requires well-considered clinical-pathologic correlation. Familiarity with the diverse architectural patterns and immunophenotype of HCC is essential; however, even in the setting of known hepatic disease, a well-developed pseudoglandular pattern may be a convincing morphologic mimic of a primary surface epithelial ovarian malignancy. We describe a diagnostically challenging case of a 50-year-old woman with metastatic HCC exhibiting a prominent pseudoglandular pattern mimicking primary endometrioid adenocarcinoma, and an approach to overcome this important pitfall.
A randomized, double-blind, placebo-controlled study of histone deacetylase type 6 inhibition for the treatment of painful diabetic peripheral neuropathy
Authors: Michelson David , Chin William W. , Dworkin Robert H. , Freeman Roy , Herrmann David N. , Mazitschek Ralph , Pop-Busui Rodica , Shaibani Aziz , Vornov James , Jones Melissa , Jarpe Matthew , Hader Brittany , Viera Theresa , Hylan Michelle , Kachmar Tim , Jones Simon
Published: November 2023

Introduction:

Current treatments for painful diabetic peripheral neuropathy (DPN) are insufficiently effective for many individuals and do not treat nonpain signs and symptoms. The enzyme histone deacetylase type 6 (HDAC6) may play a role in the pathophysiology of painful DPN, and inhibition of HDAC6 has been proposed as a potential treatment.

Objectives:

To assess the efficacy and safety of the novel HDAC6 inhibitor ricolinostat for the treatment of painful diabetic peripheral neuropathy.

Methods:

We conducted a 12-week randomized, double-blind, placebo-controlled phase 2 study of the efficacy of ricolinostat, a novel selective HDAC6 inhibitor, in 282 individuals with painful DPN. The primary outcome was the change in the patient-reported pain using a daily diary, and a key secondary outcome was severity of nonpain neuropathic signs using the Utah Early Neuropathy Scale (UENS) score.

Results:

At the 12-week assessment, changes in average daily pain and UENS scores were not different between the ricolinostat and placebo groups.

Conclusion:

These results do not support the use of the HDAC6 inhibitor ricolinostat as a treatment for neuropathic pain in DPN for periods up to 12 weeks.
Detection of Brain Metastases by Contrast-Enhanced MRI: Comparison of Gadopiclenol and Gadobenate in a Mouse Model
Authors: Robert Philippe , Vives Véronique , Rasschaert Marlène , Hao Jing , Soares Miguel , Lemaître Marjorie , Dencausse Anne , Catoen Sarah
Published: November 2023

Objectives

The aim of this study was to evaluate the capacity of gadopiclenol, a high-relaxivity gadolinium-based contrast agent to detect brain metastases in mice as a function of dose (0.08 mmol/kg or 0.1 mmol/kg) compared with gadobenate at 0.1 mmol/kg.

Materials and Methods

Brain metastases were induced by ultrasound-guided intracardiac implantation of 1.105MDA-MB-231Br cells in the left ventricle of 18 anesthetized Balb/c Nude nu/nu female mice. At day 28 ± 3 after cell injection, each mouse received 2 crossover intravenous injections at 24-hour intervals, randomly selected from 2 doses of gadopiclenol (0.08 mmol/kg or 0.1 mmol/kg) and gadobenate (0.1 mmol/kg) with n = 6 mice/group (3 groups). Brain magnetic resonance imaging sessions were performed at 4 weeks on a 2.35 T magnet with a 3-dimensional T1-weighted high-resolution gradient echo sequence, before and after each injection. Images were blindly and randomly analyzed to detect enhancing lesions. Contrast-to-noise ratio between the metastases and the surrounding healthy parenchyma was calculated, based on region-of-interest signal measurements. In 2 animals per group, an early time point was added to the protocol (day 22 ± 3) to evaluate the sensitivity of detection as a function of time. After the last imaging session, the presence and location of whole-brain metastases were confirmed by histology in 4 mice.

Results

After gadopiclenol, approximately twice as many metastases were detected compared with gadobenate, regardless of the dose. Contrast-to-noise ratios of the detected metastases were 2.3 and 3.3 times higher with gadopiclenol at 0.08 mmol/kg and 0.1 mmol/kg, respectively, compared with gadobenate at 0.1 mmol/kg (P< 0.0001). Gadopiclenol at the dose of 0.1 mmol/kg resulted in a 1.4-fold higher contrast compared with gadopiclenol at 0.08 mmol/kg (P< 0.02). In a subset of mice that were imaged 1 week earlier, 2 metastases were detected with gadopiclenol and not with gadobenate.

Conclusions

The high-relaxivity macrocyclic gadolinium-based contrast agent gadopiclenol allowed higher diagnostic performance for detecting brain enhancing metastases in terms of contrast-to-noise ratio and number of detected metastases compared with gadobenate, at both equal (0.1 mmol/kg) dose and 20% lower Gd dose (0.08 mmol/kg). Tumor detection was higher after gadopiclenol at the dose of 0.1 mmol/kg compared with 0.08 mmol/kg.
Duplications and retrogenes are numerous and widespread in modern canine genomic assemblies
Authors: Nguyen Anthony K. , Blacksmith Matthew S. , Kidd Jeffrey M.
Published: November 2023

Recent years have seen a dramatic increase in the number of canine genome assemblies available. Duplications are an important source of evolutionary novelty and are also prone to misassembly. We explored the duplication content of nine canine genome assemblies using both genome self-alignment and read-depth approaches. We find that 8.58% of the genome is duplicated in the canFam4 assembly, derived from the German Shepherd Dog Mischka, including 90.15% of unplaced contigs. Highlighting the continued difficulty in properly assembling duplications, less than half of read-depth and assembly alignment duplications overlap, but the mCanLor1.2 Greenland wolf assembly shows greater concordance. Further study shows the presence of multiple segments that have alignments to four or more duplicate copies. These high-recurrence duplications correspond to gene retrocopies. We identified 3,892 candidate retrocopies from 1,316 parental genes in the canFam4 assembly and find that approximately 8.82% of duplicated base pairs involve a retrocopy, confirming this mechanism as a major driver of gene duplication in canines. Similar patterns are found across eight other recent canine genome assemblies, with multiple metrics supporting the high-quality of the mCanLor1.2 wolf assembly constructed using PacBio HiFi reads. Comparison between the wolf and other canine assemblies found that approximately 92% of retrocopy insertions are shared between assemblies. By calculating the number of generations since genome divergence, we estimate that new retrocopy insertions appear, on average, in 1 out of 3,514 births. Together, our analyses illustrate the impact of retrogene formation on canine genomes and highlight the variable representation of duplicated sequences among recently completed canine assemblies.

Significance

Duplications are highly influential on evolution, but are commonly misassembled, especially in lagging genomic groups like canines. We assessed nine canine assemblies for duplication presence, and found enrichment for acrocentric regions, misattribution of duplications to unplaced contigs, and the presence of short, high-recurrence duplications. Investigating further, we find high numbers of retrocopies retaining hallmarks present in the canine assemblies, and determine a rate of novel retrocopy insertion at 1 in 3,514 births.
The human mitochondrial mRNA structurome reveals mechanisms of gene expression
Authors: Conor Moran J. , Brivanlou Amir , Brischigliaro Michele , Fontanesi Flavia , Rouskin Silvi , Barrientos Antoni
Published: November 2023

The mammalian mitochondrial genome encodes thirteen oxidative phosphorylation system proteins, crucial in aerobic energy transduction. These proteins are translated from 9 monocistronic and 2 bicistronic transcripts, whose native structures remain unexplored, leaving fundamental molecular determinants of mitochondrial gene expression unknown. To address this gap, we developed a mitoDMS-MaPseq approach and used DREEM clustering to resolve the native human mitochondrial mt-mRNA structurome. We gained insights into mt-mRNA biology and translation regulatory mechanisms, including a unique programmed ribosomal frameshifting for theATP8/ATP6transcript. Furthermore, absence of the mt-mRNA maintenance factor LRPPRC led to a mitochondrial transcriptome structured differently, with specific mRNA regions exhibiting increased or decreased structuredness. This highlights the role of LRPPRC in maintaining mRNA folding to promote mt-mRNA stabilization and efficient translation. In conclusion, our mt-mRNA folding maps reveal novel mitochondrial gene expression mechanisms, serving as a detailed reference and tool for studying them in different physiological and pathological contexts.
The mechanistic basis of evolutionary transitions between grey, slate, and blue colour in Tanagers (Thraupidae)
Authors: Babarovic Frane , Cooney Christopher R , Zinn Thomas , Drobniak Szymon M. , Janas Katarzyna , Kennedy Jonathan D , Nadeau Nicola J , Parnell Andrew J , Thomas Gavin Huw , Burg Stephanie
Published: November 2023

Both pigmentary and structural colours share many common elements of their feather anatomy, i.e. keratin, air and melanin packed in the melanosomes, despite utilizing different mechanisms of the colour production. This means that evolutionary transitions between pigmentary and structural colours can be achieved through a simple adjustment of these elements. Recently, an evolutionary hypothesis for the transition between pigmentary grey, through slate and finally to structural blue colour has been proposed and confirmed in the clade Tanagers on a macroevolutionary level. Here, we investigate mechanistic basis of this evolutionary pathway. By using SAXS (small-angle X-ray scattering) we have quantified important elements of spongy layer in medullary cells that is crucial for colour production by coherent scattering of light wavelengths. We have quantified five elements of the spongy layer: nanostructure complexity, average hard block thickness, average soft block thickness, filling fraction and Iovalue. We report that across different categories of feather colour, i.e. blue, slate and grey, nanostructure complexity, filling fraction and Iovalue explained variation in the chromatic component of the colour (between the three colour categories). Chromatic variation within the colour category was explained by filling fraction in the case of slate colour and by nanostructure complexity and average hard block thickness in the case of blue colour. We propose that variation in different elements or combination of elements of the spongy nanostructure has been utilised in feather colour evolution, both within and between colour categories, to overcome developmental constraints imposed by self-assembly processes.
A general prediction model for substrates of transport proteins
Authors: Kroll Alexander , Niebuhr Nico , Butler Gregory , Lercher Martin J.
Published: November 2023

Transport proteins play a crucial role in cellular metabolism and are central to many aspects of molecular biology and medicine. Determining the function of transport proteins experimentally is challenging, as they become unstable when isolated from cell membranes. Machine learning-based predictions could provide an efficient alternative. However, existing methods are limited to predicting a small number of specific substrates or broad transporter classes. These limitations stem partly from using small datasets for model training and a choice of input features that lack sufficient information about the prediction problem. Here, we present SPOT, the first general machine learning model that can successfully predict specific substrates for arbitrary transport proteins, achieving an accuracy above 92% on independent and diverse test data covering widely different transporters and a broad range of metabolites. SPOT uses Transformer Networks to represent transporters and substrates numerically. To overcome the problem of missing negative data for training, it augments a large dataset of known transporter-substrate pairs with carefully sampled random molecules as non-substrates. SPOT not only predicts specific transporter-substrate pairs, but also outperforms previously published models designed to predict broad substrate classes for individual transport proteins. We provide a web server and Python function that allows users to explore the substrate scope of arbitrary transporters.
Substantial urbanization-driven declines of larval and adult moths in a subtropical environment
Authors: Belitz Michael W. , Sawyer Asia , Hendrick Lillian , Kawahara Akito , Guralnick Robert P.
Published: November 2023

Recent work has shown the decline of insect abundance, diversity, and biomass, with potential implications for ecosystem services. These declines are especially pronounced in regions with high human activity, and urbanization is emerging as a significant contributing factor. However, the scale of these declines and the traits that determine variation in species-specific responses remain less well understood, especially in subtropical and tropical regions, where insect diversity is high and urban footprints are rapidly expanding. Here, we surveyed moths across an entire year in protected forested sites across an urbanization gradient to test how caterpillar and adult life stages of subtropical moths (Lepidoptera) are impacted by urbanization. Specifically, we assess how urban development affects the total abundance of caterpillars and adult moths, and quantify how richness and phylogenetic diversity of macro-moths are impacted by urban development. Additionally, we determine the effects of urban warming on species-specific adult macro-moth abundance while accounting for urban development and explore how life-history traits condition species’ responses to urban stressors. At the community level, we find that urban development decreases caterpillar biomass and adult moth abundance. We also find sharp declines of adults in response to urban development across the moth phylogeny, leading to a decrease in species richness and phylogenetic diversity in more urban sites. Finally, our study found that smaller macro-moths are less impacted by urban development than larger macro- moths in subtropical environments, perhaps highlighting the tradeoffs of metabolic costs of urban heat island effects favoring smaller moths over the relative benefits of dispersal for larger moths. In summary, our research underscores the far-reaching consequences of urbanization on moths and provides compelling evidence that urban forests alone may not be sufficient to safeguard biodiversity in cities.
Systems profiling reveals recurrently dysregulated cytokine signaling responses in ER+ breast cancer patients’ blood
Authors: Orcutt-Jahns Brian , Lima Junior Joao Rodrigues , Rockne Russell C. , Matache Adina , Branciamore Sergio , Hung Ethan , Rodin Andrei S. , Lee Peter P. , Meyer Aaron S.
Published: November 2023

Cytokines mediate cell-to-cell communication across the immune system and therefore are critical to immunosurveillance in cancer and other diseases. Several cytokines show dysregulated abundance or signaling responses in breast cancer, associated with the disease and differences in survival and progression. Cytokines operate in a coordinated manner to affect immune surveillance and regulate one another, necessitating a systems approach for a complete picture of this dysregulation. Here, we profiled cytokine signaling responses of peripheral immune cells from breast cancer patients as compared to healthy controls in a multidimensional manner across ligands, cell populations, and responsive pathways. We find alterations in cytokine responsiveness across pathways and cell types that are best defined by integrated signatures across dimensions. Alterations in the abundance of a cytokine’s cognate receptor do not explain differences in responsiveness. Rather, alterations in baseline signaling and receptor abundance suggesting immune cell reprogramming are associated with altered responses. These integrated features suggest a global reprogramming of immune cell communication in breast cancer.

Significance Statement

While individual cytokine responses have previously been observed to be altered in breast cancer, cytokine signaling responses are tightly interconnected in a way that has not been previously characterized. Here, we profile cytokine signaling responses and find alterations that are shared across both pathways and cell types. The signatures across these measurements better define the alterations and point to a broad immunosuppression response.

Highlights

Baseline and post-stimulation cytokine signaling profiles differ between healthy donors and breast cancer patients.

Changes in cytokine response are not explained by differences in abundance of the cognate receptor

Features of signaling response and receptor abundance dysregulation are coordinated across patients

Integrated patterns of dysregulation in breast cancer patients share features of Th17 like-response as well as regulatory-like B and CD8+T cells
LMO3 is a suppressor of the basal-like/squamous PDAC subtype and reduces disease aggressiveness of pancreatic cancer through glycerol 3-phosphate metabolism
Authors: Ohara Yuuki , Craig Amanda J. , Liu Huaitian , Yang Shouhui , Moreno Paloma , Dorsey Tiffany H. , Cawley Helen , Azizian Azadeh , Gaedcke Jochen , Ghadimi Michael , Hanna Nader , Ambs Stefan , Perwez Hussain S.
Published: November 2023

Pancreatic ductal adenocarcinoma (PDAC) encompasses diverse molecular subtypes, including the classical/progenitor and basal-like/squamous subtypes, each exhibiting distinct characteristics, with the latter known for its aggressiveness. We employed an integrative approach combining transcriptomic and metabolomic analyses to pinpoint potential genes contributing to the basal-like/squamous subtype differentiation. Applying this approach to our NCI-UMD-German and a validation cohort, we identified LIM Domain Only 3 (LMO3), a transcription co-factor, as a candidate suppressor of the basal-like/squamous subtype. Reduced LMO3 expression was significantly associated with higher pathological grade, advanced disease stage, induction of the basal-like/squamous subtype, and decreased survival among PDAC patients.In vitroexperiments demonstrated thatLMO3transgene expression inhibited PDAC cell proliferation and migration/invasion, concurrently downregulating the basal-like/squamous gene signature. Metabolomic analysis of patient tumors and PDAC cells revealed a metabolic program linked to elevated LMO3 expression and the classical/progenitor subtype, characterized by enhanced lipogenesis and suppressed amino acid metabolism. Notably, glycerol 3-phosphate (G3P) levels positively correlated with LMO3 expression and associated with improved patient survival. Furthermore, glycerol-3-phosphate dehydrogenase 1 (GPD1), a crucial enzyme in G3P synthesis, showed upregulation in LMO3-high and classical/progenitor PDAC, suggesting its potential role in mitigating disease aggressiveness. Collectively, our findings suggest that heightened LMO3 expression reduces transcriptomic and metabolomic characteristics indicative of basal-like/squamous tumors with decreased disease aggressiveness in PDAC patients. The observations describe LMO3 as a candidate for diagnostic and therapeutic targeting in PDAC.

Graphical abstract

Highlights

LMO3 is downregulated in basal-like/squamous PDAC while its expression is maintained in the classical/progenitor PDAC subtype

Upregulated LMO3 expression correlates with improved PDAC survival and reduced proliferation and migration/invasion in PDAC cells

Upregulated LMO3 suppresses basal-like/squamous differentiation and induces a unique metabolic signature characterized by elevated lipogenesis and diminished amino acid metabolism, resembling the classical/progenitor PDAC subtype

Enhanced LMO3 expression associates with elevated glycerol 3-phosphate levels in PDAC, correlating with improved patient survival in PDAC
Chromosome-level genome assemblies of two hemichordates provide new insights into deuterostome origin and chromosome evolution
Authors: Lin Che-Yi , Marlétaz Ferdinand , Pérez-Posada Alberto , Martínez García Pedro Manuel , Schloissnig Siegfried , Peluso Paul , Conception Greg T. , Bump Paul , Chen Yi-Chih , Chou Cindy , Lin Ching-Yi , Fan Tzu-Pei , Tsai Chang-Tai , Gómez Skarmeta José Luis , Tena Juan J. , Lowe Christopher J. , Rank David R. , Rokhsar Daniel S. , Yu Jr-Kai , Su Yi-Hsien
Published: November 2023

Deuterostomes are an animal superphylum that includes Hemichordata and Echinodermata (together Ambulacraria) and Chordata. The diversity of deuterostome body plans has made it challenging to reconstruct their ancestral condition and to decipher the genetic changes that drove the diversification of deuterostome lineages. Here, we generate chromosome-level genome assemblies of two hemichordate species,Ptychodera flavaandSchizocardium californicum, and use comparative genomic approaches to infer the chromosomal architecture of the deuterostome common ancestor and delineate lineage-specific chromosomal modifications. We show that hemichordate chromosomes (1N=23) exhibit remarkable chromosome-scale macrosynteny when compared to other deuterostomes, and can be derived from 24 deuterostome ancestral linkage groups (ALGs). These deuterostome ALGs in turn match previously inferred bilaterian ALGs, consistent with a relatively short transition from the last common bilaterian ancestor to the origin of deuterostomes. Based on this deuterostome ALG complement, we deduced chromosomal rearrangement events that occurred in different lineages. For example, a fusion-with-mixing event produced an Ambulacraria-specific ALG that subsequently split into two chromosomes in extant hemichordates, while this homologous ALG further fused with another chromosome in sea urchins. Orthologous genes distributed in these rearranged chromosomes are enriched for functions in various developmental processes. We found that the deeply conserved Hox clusters are located in highly rearranged chromosomes but have lower densities of transposable elements within the clusters. We also provide evidence that the deuterostome-specific pharyngeal gene cluster was established via the combination of three pre-assembled microsyntenic blocks. We suggest that since chromosomal rearrangement events and formation of new gene clusters may change the regulatory controls of developmental genes, these events may have contributed to the evolution of diverse body plans among deuterostomes.
Recruitment of FBXO22 for Targeted Degradation of NSD2
Authors: Nie David Y. , Tabor John R. , Li Jianping , Kutera Maria , St-Germain Jonathan , Hanley Ronan P. , Wolf Esther , Paulakonis Ethan , Kenney Tristan M.G. , Duan Shili , Shrestha Suman , Owens Dominic D.G. , Pon Ailing , Szewczyk Magdalena , Lamberto Anthony Joseph , Menes Michael , Li Fengling , Barsyte-Lovejoy Dalia , Brown Nicholas G. , Barsotti Anthony M. , Stamford Andrew W. , Collins Jon L. , Wilson Derek J. , Raught Brian , Licht Jonathan D. , James Lindsey I. , Arrowsmith Cheryl H.
Published: November 2023

Targeted protein degradation (TPD) is an emerging therapeutic strategy that would benefit from new chemical entities with which to recruit a wider variety of ubiquitin E3 ligases to target proteins for proteasomal degradation. Here, we describe a TPD strategy involving the recruitment of FBXO22 to induce degradation of the histone methyltransferase and oncogene NSD2. UNC8732 facilitates FBXO22-mediated degradation of NSD2 in acute lymphoblastic leukemia cells harboring the NSD2 gain of function mutation p.E1099K, resulting in growth suppression, apoptosis, and reversal of drug resistance. The primary amine of UNC8732 is metabolized to an aldehyde species, which engages C326 of FBXO22 in a covalent and reversible manner to recruit the SCFFBXO22Cullin complex. We further demonstrate that a previously reported alkyl amine-containing degrader targeting XIAP is similarly dependent on SCFFBXO22. Overall, we present a highly potent NSD2 degrader for the exploration of NSD2 disease phenotypes and a novel FBXO22-dependent TPD strategy.
Mediterranean Diet Protects Against a Neuroinflammatory Cortical Transcriptome: Associations with Brain Volumetrics, Peripheral Inflammation, Social Isolation and Anxiety
Authors: Negrey Jacob D. , Frye Brett M. , Johnson Corbin S.C. , Kim Jeongchul , Barcus Richard A. , Lockhart Samuel N. , Whitlow Christopher T. , Sutphen Courtney , Chiou Kenneth L. , Snyder-Mackler Noah , Montine Thomas J. , Craft Suzanne , Shively Carol A. , Register Thomas C.
Published: November 2023

INTRODUCTION

Mediterranean diets may be neuroprotective and prevent cognitive decline relative to Western diets, however the underlying biology is poorly understood.

METHODS

We assessed the effects of Western vs. Mediterranean-like diets on RNAseq generated transcriptional profiles in temporal cortex and their relationships with changes in MRI neuroimaging phenotypes, circulating monocyte gene expression, and observations of social isolation and anxiety in 38 socially-housed, middle-aged female cynomolgus macaques.

RESULTS

Diet resulted in differential expression of seven transcripts (FDR<0.05). Cyclin dependent kinase 14 (CDK14), a proinflammatory regulator, was lower in the Mediterranean group. The remaining six transcripts [i.e., “lunatic fringe” (LFNG), mannose receptor C type 2 (MRC2), solute carrier family 3 member 2 (SLCA32), butyrophilin subfamily 2 member A1 (BTN2A1), katanin regulatory subunit B1 (KATNB1), and transmembrane protein 268 (TMEM268)] were higher in cortex of the Mediterranean group and generally associated with anti-inflammatory/neuroprotective pathways.KATNB1encodes a subcomponent of katanin, important in maintaining microtubule homeostasis.BTN2A1is involved in immunomodulation of γδ T-cells which have anti-neuroinflammatory and neuroprotective effects.CDK14,LFNG,MRC2,andSLCA32are associated with inflammatory pathways. The latter four differentially expressed cortex transcripts were associated with monocyte transcript levels, changes in AD-relevant brain volumes determined by MRI over the course of the study, and social isolation and anxiety.CDK14was positively correlated with monocyte inflammatory transcripts, changes in total brain, gray matter, cortical gray matter volumes, and time alone and anxious behavior, and negatively correlated with changes in total white matter and cerebrospinal fluid (CSF) volumes. In contrast,LFNG,MRC2, andSLCA32were negatively correlated with monocyte inflammatory transcripts and changes in total gray matter volume, and positively correlated with CSF volume changes, and SLCA32 was negatively correlated with time alone.

DISCUSSION

Collectively, our results suggest that relative to Western diets, Mediterranean diets confer protection against peripheral and central inflammation which is reflected in preserved brain structure and behavior.
Neuropeptide Signaling is Required to Implement a Line Attractor Encoding a Persistent Internal Behavioral State
Authors: Mountoufaris George , Nair Aditya , Yang Bin , Kim Dong-Wook , Anderson David J.
Published: November 2023

Internal states drive survival behaviors, but their neural implementation is not well understood. Recently we identified a line attractor in the ventromedial hypothalamus (VMH) that represents an internal state of aggressiveness. Line attractors can be implemented by recurrent connectivity and/or neuromodulatory signaling, but evidence for the latter is scant. Here we show that neuropeptidergic signaling is necessary for line attractor dynamics in this system, using a novel approach that integrates cell type-specific, anatomically restricted CRISPR/Cas9-based gene editing with microendoscopic calcium imaging. Co-disruption of receptors for oxytocin and vasopressin in adult VMH Esr1+neurons that control aggression suppressed attack, reduced persistent neural activity and eliminated line attractor dynamics, while only modestly impacting neural activity and sex- or behavior-tuning. These data identify a requisite role for neuropeptidergic signaling in implementing a behaviorally relevant line attractor. Our approach should facilitate mechanistic studies in neuroscience that bridge different levels of biological function and abstraction.
Sequential Modelling for Medical Image Segmentation
Authors: How Chun Hung , Rajapakse Jagath C.
Published: November 2023

An image can be seen as a long sequence of tokens with spatial structure hence an image segmentation task can be treated as a sequence-to-sequence task. Existing attention-based segmentation models have incorporated an up-sampling module at the pixel decoder, such design assumed the backbone to have multiple feature scales. Furthermore, the existing models did not emphasize the ability of sequential modelling for multi-tasking. In this paper, we propose to model image segmentation task as a long sequence prediction task with an improvisation on MegaByte. As MegaByte efficiently reduced the self-attention cost using multi-scale structure known as global and local models, we train two MegaByte models as an encoder and decoder for multi-tasking. Our multi-task model allows different segmentation tasks to be trained simultaneously and inferenced with a task prompt. The encoder takes in the image sequence to encode them as a key while the decoder takes in the conditional input as a query. As decoder conditional input is usually sparser than the image, we use a relatively shallow decoder. We demonstrate our method on segmentation of intracranial haemorrhages from computed tomography (CT) head scans and show comparable performance to existing models. On a brain tissue segmentation task on CT images, our method outperformed the existing methods especially on tiny structure.

Clinical relevance

CT images are the first line of head scans when stroke or haemorrhage is suspected. Segmentation of intracranial haemorrhages (ICH) can provide clinicians with important measures of brain lesions to decide on treatment procedure or surgical decision. Brain and tissue volumes are indicative of neurodegenerative diseases. The proposed techniques can be used to segment ICH and brain tissues from CT head scans.
Sida cordifolia, a medicinal plant, is efficacious in models of Huntington’s disease by reducing ER stress
Authors: Simha Prasanna K , Mukherjee Chandramouli , Bhatia Karishma , Gupta Vikas Kumar , Sapariya Neerav M , Nagar Padmanabhi , Azim Nazeer ZA , Godbole Ashwini , Sahu Bhavani Shankar , Upadhyay Sanjeev K
Published: November 2023

Background and aim

Huntington’s Disease is a severe neurodegenerative disorder caused by misfolded mutant huntingtin proteins with expanded stretches of polyglutamines aggregating and destroying cells in the nervous system.Sida cordifoliaandAcorus calamusare medicinal plants used in traditional Ayurvedic medicine to treat neurological disorders. Here, we tested the effectiveness of extracts of both medicinal plants in decreasing aggregation of mutant huntingtin protein in models of Huntington’s Disease and explored the mode of action.

Experimental procedure

We used two models, the nematodeCaenorhabditis elegansand a transgenic mouse neuroblastoma cell line, both expressing mutant huntingtin proteins with elongated polyglutamines. We assessed the effect ofSida cordifoliaandAcorus calamuson mutant huntingtin protein aggregation in both models, and additionally used the cell line for mechanistic studies to identify cellular pathways underlying the effects of treatment.

Results and conclusion

Here, we show that an extract ofSida cordifoliainhibits aggregation of mutant huntingtin proteins. In theC. elegansmodel, the extract prolonged life span and improved motility of the nematode by reducing aggregation of the mutant huntingtin protein.Acorus calamusdid not exhibit these effects. In the transgenic mouse neuroblastoma cell line, the extract decreased aggregation of the mutant huntingtin protein by suppressing key pathways in the ER stress response caused by the mutant protein. Our results highlight the potential therapeutic value ofSida cordifoliaand its promise as a source for novel medications.

Highlights

Sida cordifoliaextract reduces aggregates in HD model of transgenic worms

Reduction in aggregates leads to improved motility and longevity

Sida cordifoliaextract reduces ER stress in cells expressing mHTT protein

First report on the pharmacology ofSida cordifoliain neurodegeneration