A deep position-encoding model for predicting olfactory perception from molecular structures and electrostatics.

Predicting olfactory perceptions from odorant molecules is challenging due to the complex and potentially discontinuous nature of the perceptual space for smells. In this study, we introduce a deep learning model, Mol-PECO (Molecular Representation by Positional Encoding of Coulomb Matrix), designed to predict olfactory perceptions based on molecular structures and electrostatics. Mol-PECO learns the efficient embedding of molecules by utilizing the Coulomb matrix, which encodes atomic coordinates and charges, as an alternative of the adjacency matrix and its Laplacian eigenfunctions as positional encoding of atoms. With a comprehensive dataset of odor molecules and descriptors, Mol-PECO outperforms traditional machine learning methods using molecular fingerprints and graph neural networks based on adjacency matrices. The learned embeddings by Mol-PECO effectively capture the odor space, enabling global clustering of descriptors and local retrieval of similar odorants. This work contributes to a deeper understanding of the olfactory sense and its mechanisms.

Corrigendum: Melanoma of the dog and cat: consensus and guidelines.

[This corrects the article DOI: 10.3389/fvets.2024.1359426.].

Information geometric bound on general chemical reaction networks.

We investigate the convergence of chemical reaction networks (CRNs), aiming to establish an upper bound on their reaction rates. The nonlinear characteristics and discrete composition of CRNs pose significant challenges in this endeavor. To circumvent these complexities, we adopt an information geometric perspective, utilizing the natural gradient to formulate a nonlinear system. This system effectively determines an upper bound for the dynamics of CRNs. We corroborate our methodology through numerical simulations, which reveal that our constructed system converges more rapidly than CRNs within a particular class of reactions. This class is defined by the count of chemicals, the highest stoichiometric coefficients in the reactions, and the total number of reactions involved. Further, we juxtapose our approach with traditional methods, illustrating that the latter falls short in providing an upper bound for CRN reaction rates. Although our investigation centers on CRNs, the widespread presence of hypergraphs across various disciplines, ranging from natural sciences to engineering, indicates potential wider applications of our method, including in the realm of information science.

Melanoma of the dog and cat: consensus and guidelines.

Melanoma of the dog and cat poses a clinical challenge to veterinary practitioners across the globe. As knowledge evolves, so too do clinical practices. However, there remain uncertainties and controversies. There is value for the veterinary community at large in the generation of a contemporary wide-ranging guideline document. The aim of this project was therefore to assimilate the available published knowledge into a single accessible referenced resource and to provide expert clinical guidance to support professional colleagues as they navigate current melanoma challenges and controversies. Melanocytic tumors are common in dogs but rare in cats. The history and clinical signs relate to the anatomic site of the melanoma. Oral and subungual malignant melanomas are the most common malignant types in dogs. While many melanocytic tumors are heavily pigmented, making diagnosis relatively straightforward, melanin pigmentation is variable. A validated clinical stage scheme has been defined for canine oral melanoma. For all other locations and for feline melanoma, TNM-based staging applies. Certain histological characteristics have been shown to bear prognostic significance and can thus prove instructive in clinical decision making. Surgical resection using wide margins is currently the mainstay of therapy for the local control of melanomas, regardless of primary location. Radiotherapy forms an integral part of the management of canine oral melanomas, both as a primary and an adjuvant therapy. Adjuvant immunotherapy or chemotherapy is offered to patients at high risk of developing distant metastasis. Location is the major prognostic factor, although it is not completely predictive of local invasiveness and metastatic potential. There are no specific guidelines regarding referral considerations for dogs with melanoma, as this is likely based on a multitude of factors. The ultimate goal is to provide the best options for patients to extend quality of life and survival, either within the primary care or referral hospital setting.

Familial cryptogenic stroke.

Familial cryptogenic stroke associated with atrial septal defect and patent foramen ovale is rare. The presence of a family history of cryptogenic stroke may lead to the requirement for careful follow-up for younger family members.

Importance of modifiable non-radiographic functional parameters for adult spinal deformity.

We clarified non-radiographic physical parameters associated with the severity of adult spinal deformity (ASD) using community-dwelling adult volunteers. They were subjected to upright entire spine radiographs for standard radiographic parameters and the number of sagittal modifiers of SRS-Schwab ASD classification (Schwab-SM). Clinical evaluations included isometric muscle strength of trunk extensor (TEX), trunk flexor (TFL), quadriceps femoris (QF), gluteus maximus, and iliopsoas; range of motion (ROM) of hip, knee, ankle, and active back extension (BET); SF36 physical component score (PCS), VAS for back and knee pain, and the degree of ambulatory kyphosis (dTIA). Each muscle strength was calibrated by body weight (BW) and expressed as BW ratio. According to our previous study, dTIA ≥ 7.6° was defined as pathological and dTIA ≤ 3.5° as normal. A final total of 409 female volunteers were included, and their demographics were; age 67.0 ± 5.5 years, Schwab-SM 2.1 ± 1.8, TEX 0.90 ± 0.33BW, TFL 0.48 ± 0.15BW, QF 0.45 ± 0.19BW, PCS 33.5 ± 6.5. Subjects were classified as clinical ASD group (cASD, n = 10) with PCS ≤ 27(mean-1SD) and pathological dTIA, robust group (n = 19) with PCS ≥ 40 (mean + 1SD) and normal dTIA, and the rest (non-cASD, n = 338). Statistical analyses showed significant differences in TEX, TFL, QF, knee extension (KEX), and BET between robust and cASD, and the mean values of robust group (TEX ≥ 1.1BW, TFL ≥ 0.5BW, QF ≥ 0.5BW, KEX ≥ 0° and BET ≥ 14 cm) were used as 'ASD-MJ' index. Subjects with fully achieving ASD-MJ goals showed significantly better radiographic and clinical outcomes than those with unmet goals. In conclusion, upon prescribing conservative or physical therapies for ASD patients, modifiable clinical goals should be clarified, and ASD-MJ could be a benchmark.

Tracking of Internal Granular Progenitors Responding to Valproic Acid in the Cerebellar Cortex of Infant Ferrets.

Internal granular progenitors (IGPs) in the developing cerebellar cortex of ferrets differentiate towards neural and glial lineages. The present study tracked IGPs that proliferated in response to valproic acid (VPA) to determine their fate during cerebellar cortical histogenesis. Ferret kits were used to administer VPA (200 µg/g body weight) on postnatal days 6 and 7. EdU and BrdU were injected on postnatal days 5 and 7, respectively, to label the post-proliferative and proliferating cells when exposed to VPA. At postnatal day 20, when the external granule layer was most expanded, EdU- and BrdU-single-labeled cells were significantly denser in the inner granular layer of VPA-exposed ferrets than in controls. No EdU- or BrdU-labeling was found in Purkinje cells and molecular layer interneurons. Significantly higher percentages of NeuN and Pax6 immunostaining in VPA-exposed ferrets revealed VPA-induced differentiation of IGPs towards granular neurons in BrdU-single-labeled cells. In contrast, both EdU- and BrdU-single-labeled cells exhibited significantly greater percentages of PCNA immunostaining, which appeared in immature Bergman glia, in the internal granular layer of VPA-exposed ferrets. These findings suggest that VPA affects the proliferation of IGPs to induce differentiative division towards granular neurons as well as post-proliferative IGPs toward differentiation into Bergmann glia.

Generating PET Attenuation Maps via Sim2Real Deep Learning-Based Tissue Composition Estimation Combined with MLACF.

Deep learning (DL) has recently attracted attention for data processing in positron emission tomography (PET). Attenuation correction (AC) without computed tomography (CT) data is one of the interests. Here, we present, to our knowledge, the first attempt to generate an attenuation map of the human head via Sim2Real DL-based tissue composition estimation from model training using only the simulated PET dataset. The DL model accepts a two-dimensional non-attenuation-corrected PET image as input and outputs a four-channel tissue-composition map of soft tissue, bone, cavity, and background. Then, an attenuation map is generated by a linear combination of the tissue composition maps and, finally, used as input for scatter+random estimation and as an initial estimate for attenuation map reconstruction by the maximum likelihood attenuation correction factor (MLACF), i.e., the DL estimate is refined by the MLACF. Preliminary results using clinical brain PET data showed that the proposed DL model tended to estimate anatomical details inaccurately, especially in the neck-side slices. However, it succeeded in estimating overall anatomical structures, and the PET quantitative accuracy with DL-based AC was comparable to that with CT-based AC. Thus, the proposed DL-based approach combined with the MLACF is also a promising CT-less AC approach.

Mitochondrial protein C15ORF48 is a stress-independent inducer of autophagy that regulates oxidative stress and autoimmunity.

Autophagy is primarily activated by cellular stress, such as starvation or mitochondrial damage. However, stress-independent autophagy is activated by unclear mechanisms in several cell types, such as thymic epithelial cells (TECs). Here we report that the mitochondrial protein, C15ORF48, is a critical inducer of stress-independent autophagy. Mechanistically, C15ORF48 reduces the mitochondrial membrane potential and lowers intracellular ATP levels, thereby activating AMP-activated protein kinase and its downstream Unc-51-like kinase 1. Interestingly, C15ORF48-dependent induction of autophagy upregulates intracellular glutathione levels, promoting cell survival by reducing oxidative stress. Mice deficient in C15orf48 show a reduction in stress-independent autophagy in TECs, but not in typical starvation-induced autophagy in skeletal muscles. Moreover, C15orf48-/- mice develop autoimmunity, which is consistent with the fact that the stress-independent autophagy in TECs is crucial for the thymic self-tolerance. These results suggest that C15ORF48 induces stress-independent autophagy, thereby regulating oxidative stress and self-tolerance.

Gene expression profiles associated with early relapse during first remission induction in canine multicentric high-grade B-cell lymphoma.

Although chemotherapy using CHOP-based protocol induces remission in most cases of canine multicentric high-grade B-cell lymphoma (mhBCL), some cases develop early relapse during the first induction protocol. In this study, we examined the gene expression profiles of canine mhBCL before chemotherapy and investigated their associations with early relapse during the first whole CHOP-based protocol. Twenty-five cases of mhBCL treated with CHOP-based protocol as first induction chemotherapy were included in this study. Sixteen cases completed the first whole CHOP-based protocol without relapse (S-group), and nine developed relapse during the chemotherapy (R-group). RNA-seq was performed on samples from neoplastic lymph nodes. Differentially expressed genes (DEGs) were extracted by the comparison of gene expression profiles between S- and R-groups, and the differences in the expression levels of these genes were validated by RT-qPCR. Extracted 179 DEGs included the genes related to chemokine CC motif ligand, T-cell receptor signaling pathway, and PD-L1 expression and PD-1 checkpoint pathway. We focused on chemokine CC motif ligand, and CCL4 was confirmed to be significantly downregulated in the R-group (P=0.039). We also focused on the genes related to T-cell signaling pathway, and CD3E (P=0.039), ITK (P=0.023), and LAT (P=0.023) genes were confirmed to be significantly upregulated in the R-group. The current results suggest that both changes in tumor cells and the interactions between tumor cells and immune cells are associated with the efficacy of the chemotherapy for first remission induction.

High-quality genome of the zoophytophagous stink bug, Nesidiocoris tenuis, informs their food habit adaptation.

The zoophytophagous stink bug, Nesidiocoris tenuis, is a promising natural enemy of micro-pests such as whiteflies and thrips. This bug possesses both phytophagous and entomophagous food habits, enabling it to obtain nutrition from both plants and insects. This trait allows us to maintain its population density in agricultural fields by introducing insectary plants, even when the pest prey density is extremely low. However, if the bugs' population becomes too dense, they can sometimes damage crop plants. This dual character seems to arise from the food preferences and chemosensation of this predator. To understand the genomic landscape of N. tenuis, we examined the whole genome sequence of a commercially available Japanese strain. We used long-read sequencing and Hi-C analysis to assemble the genome at the chromosomal level. We then conducted a comparative analysis of the genome with previously reported genomes of phytophagous and hematophagous stink bugs to focus on the genetic factors contributing to this species' herbivorous and carnivorous tendencies. Our findings suggest that the gustatory gene set plays a pivotal role in adapting to food habits, making it a promising target for selective breeding. Furthermore, we identified the whole genomes of microorganisms symbiotic with this species through genomic analysis. We believe that our results shed light on the food habit adaptations of N. tenuis and will accelerate breeding efforts based on new breeding techniques for natural enemy insects, including genomics and genome editing.

Induction of cerebellar cortical neurogenesis immediately following valproic acid exposure in ferret kits.

Introduction: Valproic acid (VPA) is an anticonvulsant/antiepileptic drug that regulates neurogenesis. Its effects vary depending on the timing of exposure and the types of neural progenitors involved. Neonatal exposure to VPA causes autism spectrum disorder-like behaviors in some mammalian species, including ferrets. Ferrets experience the cerebellar cortical histogenesis during early postnatal period. However, no studies have evaluated the effect of VPA on cerebellar corticohistogenesis. The present study aimed to determine the effects of VPA exposure on the developing cerebellar cortex in ferret kits with a particular focus on the cortical neurogenesis. Methods: The experimental kits each received an intraperitoneal injection of VPA, 200 µg/g body weight, on postnatal days 6 and 7. EdU and BrdU were administered on postnatal days 5 and 7, respectively, to label cells proliferating prior to and following exposure to VPA. Results: We found that 2 h post BrdU injection, BrdU-labeled cells were abundantly distributed in the internal granular layer (IGL), whereas EdU-labeled cells were primarily relegated to the inner pre-migratory zone of the external granular layer (EGL). The density of BrdU-single-labeled cells was significantly lower in the EGL and significantly higher in the IGL of the VPA-exposed group, as compared to the control group. Immunostaining for doublecortin, a marker of immature neurons, was observed in BrdU-single-labeled cells in the IGL of the VPA-exposed group, which was significantly higher than that observed in the control group. EdU-single-labeled cells that had proliferated prior to VPA exposure were also detected in the IGL. While the cell density remained unchanged, significant changes were observed in the proportions of EdU-single-labeled cells immunostained with marker antigens; higher proportion of PCNA immunostaining, but lower proportion of S100 immunostaining in the VPA-exposed group compared to the control group. Discussion: These findings suggest the presence of progenitors in the IGL of the developing cerebellar cortex in ferret kits. We called them "internal granular progenitors." The progenitors may proliferate in response to VPA, leading the differentiated lineage more toward neurons than to glial cells. Thus, VPA may facilitate the differentiative division of internal granular progenitors to produce cerebellar granular neurons.

Population dynamics models for various forms of adaptation.

Adaptability to changing environments is one of the universal characteristics of living organisms. Because individual modes of adaptation are diverse, a unified understanding of these diverse modes is essential to comprehend adaptation. Adaptations can be categorized from at least two perspectives with respect to information. One is the passivity and activity of adaptation and the other is the type of information transmission. In Darwinian natural selection, organisms are selected among randomly generated traits under which individual organisms are passive in the sense that they do not process any environmental information. On the other hand, organisms can also adapt by sensing their environment and changing their traits. This is an active adaptation in that it makes use of environmental information. In terms of information transfer, adaptation through phenotypic heterogeneity, such as bacterial bet-hedging, is intragenerational in which traits are not passed on to the next generation. In contrast, adaptation through genetic diversity is intergenerational. The theory of population dynamics enables us to unify these various modes of adaptations and their properties can be analyzed qualitatively and quantitatively using techniques from quantitative genetics and information thermodynamics. In addition, such methods can be applied to situations where organisms can learn from past experiences and pass them on from generation to generation. In this work, we introduce the unified theory of biological adaptation based on population dynamics and show its potential applications to evaluate the fitness value of information and to analyze experimental lineage tree data. Finally, we discuss future perspectives for its development. This review article is an extended version of the Japanese article in SEIBUTSU BUTSURI Vol. 57, p. 287-290 (2017).

T-cell receptor repertoire analysis of CD4-positive T cells from blood and an affected organ in an autoimmune mouse model.

One hallmark of some autoimmune diseases is the variability of symptoms among individuals. Organs affected by the disease differ between patients, posing a challenge in diagnosing the affected organs. Although numerous studies have investigated the correlation between T cell antigen receptor (TCR) repertoires and the development of infectious and immune diseases, the correlation between TCR repertoires and variations in disease symptoms among individuals remains unclear. This study aimed to investigate the correlation of TCRα and ß repertoires in blood T cells with the extent of autoimmune signs that varies among individuals. We sequenced TCRα and ß of CD4+ CD44high CD62Llow T cells in the blood and stomachs of mice deficient in autoimmune regulator (Aire) (AIRE KO), a mouse model of human autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Data analysis revealed that the degree of similarity in TCR sequences between the blood and stomach varied among individual AIRE KO mice and reflected the extent of T cell infiltration in the stomach. We identified a set of TCR sequences whose frequencies in blood might correlate with extent of the stomach manifestations. Our results propose a potential of using TCR repertoires not only for diagnosing disease development but also for diagnosing affected organs in autoimmune diseases.

Acute irradiation causes a long-term disturbance in the heterogeneity and gene expression profile of medullary thymic epithelial cells.

The thymus has the ability to regenerate from acute injury caused by radiation, infection, and stressors. In addition to thymocytes, thymic epithelial cells in the medulla (mTECs), which are crucial for T cell self-tolerance by ectopically expressing and presenting thousands of tissue-specific antigens (TSAs), are damaged by these insults and recover thereafter. However, given recent discoveries on the high heterogeneity of mTECs, it remains to be determined whether the frequency and properties of mTEC subsets are restored during thymic recovery from radiation damage. Here we demonstrate that acute total body irradiation with a sublethal dose induces aftereffects on heterogeneity and gene expression of mTECs. Single-cell RNA-sequencing (scRNA-seq) analysis showed that irradiation reduces the frequency of mTECs expressing AIRE, which is a critical regulator of TSA expression, 15 days after irradiation. In contrast, transit-amplifying mTECs (TA-mTECs), which are progenitors of AIRE-expressing mTECs, and Ccl21a-expressing mTECs, were less affected. Interestingly, a detailed analysis of scRNA-seq data suggested that the proportion of a unique mTEC cluster expressing Ccl25 and a high level of TSAs was severely decreased by irradiation. In sum, we propose that the effects of acute irradiation disrupt the heterogeneity and properties of mTECs over an extended period, which potentially leads to an impairment of thymic T cell selection.

Neonatal Exposure to Lipopolysaccharide Promotes Neurogenesis of Subventricular Zone Progenitors in the Developing Neocortex of Ferrets.

Lipopolysaccharide (LPS) is a natural agonist of toll-like receptor 4 that serves a role in innate immunity. The current study evaluated the LPS-mediated regulation of neurogenesis in the subventricular zone (SVZ) progenitors, that is, the basal radial glia and intermediate progenitors (IPs), in ferrets. Ferret pups were subcutaneously injected with LPS (500 µg/g of body weight) on postnatal days (PDs) 6 and 7. Furthermore, 5-ethynyl-2'-deoxyuridine (EdU) and 5-bromo-2'-deoxyuridine (BrdU) were administered on PDs 5 and 7, respectively, to label the post-proliferative and proliferating cells in the inner SVZ (iSVZ) and outer SVZ (oSVZ). A significantly higher density of BrdU single-labeled proliferating cells was observed in the iSVZ of LPS-exposed ferrets than in controls but not in post-proliferative EdU single-labeled and EdU/BrdU double-labeled self-renewing cells. BrdU single-labeled cells exhibited a lower proportion of Tbr2 immunostaining in LPS-exposed ferrets (22.2%) than in controls (42.6%) and a higher proportion of Ctip2 immunostaining in LPS-exposed ferrets (22.2%) than in controls (8.6%). The present findings revealed that LPS modified the neurogenesis of SVZ progenitors. Neonatal LPS exposure facilitates the proliferation of SVZ progenitors, followed by the differentiation of Tbr2-expressing IPs into Ctip2-expressing immature neurons.

Clinical features and prognosis of retroperitoneal hemangiosarcoma in dogs with surgical resection with or without adjuvant doxorubicin.

Retroperitoneal hemangiosarcoma (RPHSA) is a rare tumor in dogs with a poorly understood prognosis after surgery. The objectives of this study were to investigate the clinical features and prognosis of canine RPHSA that had undergone surgical resection. In this single-center, retrospective cohort study, we reviewed the medical records of dogs that had undergone surgical resection for retroperitoneal tumors and received a histopathologic diagnosis of HSA between 2005 and 2021. The median progression-free survival (PFS) and overall survival (OS) were 77.5 days and 168 days, respectively. In the present study, canine RPHSA had an aggressive biological behavior similar to visceral HSA. Further studies in larger canine populations are needed to evaluate the efficacy of adjuvant chemotherapy.

Safety and pharmacokinetics of thalidomide in tumor-bearing dogs.

Thalidomide, an angiogenesis inhibitor, has recently been used to treat malignant canine tumors. This study retrospectively investigated the adverse events (AEs) of thalidomide administered to tumor-bearing dogs. We investigated the pharmacokinetics of thalidomide after administration and the rate of body weight change before and after administration. The initial thalidomide dose was 5 mg/kg per os once daily, which was increased to 10 mg/kg once daily in dogs with no significant AEs. Pharmacokinetics were measured in four dogs after the 5 mg/kg or 10 mg/kg dose. We evaluated AEs related to clinical signs in 51 patients; 9/51 had lethargy, 6/51 had tremor, 4/51 had dizziness, 31/51 had decreased appetite, 8/51 had vomiting, and 16/49 had soft stool/diarrhea. We evaluated hematologic toxicity in 44 patients with grade 3 or higher adverse events; 1/44 had thrombocytopenia, 1/44 had increased blood urea nitrogen concentrations, and 5/44 had increased alanine aminotransferase activities. The mean thalidomide blood levels were Cmax=1.4 ± 0.7 µg/mL (Area under the curve [AUC]0-24=8.5 ± 4.7 µg•hr /mL) and Cmax=3.2 ± 2.1 µg/mL (AUC0-24=22.0 ± 14.7 µg•hr/mL) in the 5 mg/kg and 10 mg/kg groups, respectively. The Cmax and AUC in the 10 mg/kg group were comparable to the effective blood concentrations seen in humans administered thalidomide. The weight fluctuation rates were assessed in 24 dogs approximately 1 month after the start of thalidomide administration; more than half showed weight maintenance or gain. Most AEs were clinically acceptable; however, peripheral nerve signs were seen in some dogs.

Molecular Cloning, Expression Analyses, and Physiological Roles of Cathelicidins in the Bursa of Fabricius of the Japanese Quail, Coturnix japonica.

Antimicrobial peptides (AMPs) act directly on pathogens and maintain the anti-inflammatory effects and activation of immunocompetent cells. Therefore, the activation of the immune system in poultry via the elevation of endogenous AMPs has been attempted. In this study, we focused on the host defense mechanisms in the bursa of Fabricius (BF) of Japanese quail, cloned the cDNA of cathelicidin (CATH)-1 to -3, and analyzed their expression sites. In situ hybridization experiments revealed the mRNA expression of the CATHs in the interfollicular epithelium surrounding the lumen of the quail BF, which suggests that each CATH may exert its antimicrobial action directly in the BF. The intravenous injection of bacterial lipoteichoic acid and lipopolysaccharide endotoxins into the quail promoted the mRNA expression of CATH-1 and CATH-3 in the BF. The addition of CATH-1 or CATH-2 at the time of the antigen injection into mice resulted in antiserum with high antibody titers. Ad libitum administration of butyrate, a short-chain fatty acid, in the drinking water induced an increase in CATH-2 mRNA expression in the BF under certain conditions. These results may improve the defense mechanisms of quail by stimulating CATH expression in the BF through their diet.