Extracellular vesicles from the microalga Tetraselmis chuii are biocompatible and exhibit unique bone tropism along with antioxidant and anti-inflammatory properties.

Extracellular vesicles (EVs) are membrane-enclosed bio-nanoparticles secreted by cells and naturally evolved to transport various bioactive molecules between cells and even organisms. These cellular objects are considered one of the most promising bio-nanovehicles for the delivery of native and exogenous molecular cargo. However, many challenges with state-of-the-art EV-based candidates as drug carriers still exist, including issues with scalability, batch-to-batch reproducibility, and cost-sustainability of the final therapeutic formulation. Microalgal extracellular vesicles, which we named nanoalgosomes, are naturally released by various microalgal species. Here, we evaluate the innate biological properties of nanoalgosomes derived from cultures of the marine microalgae Tetraselmis chuii, using an optimized manufacturing protocol. Our investigation of nanoalgosome biocompatibility in preclinical models includes toxicological analyses, using the invertebrate model organism Caenorhabditis elegans, hematological and immunological evaluations ex vivo and in mice. We evaluate nanoalgosome cellular uptake mechanisms in C. elegans at cellular and subcellular levels, and study their biodistribution in mice with accurate space-time resolution. Further examination highlights the antioxidant and anti-inflammatory bioactivities of nanoalgosomes. This holistic approach to nanoalgosome functional characterization demonstrates that they are biocompatible and innate bioactive effectors with unique bone tropism. These findings suggest that nanoalgosomes have significant potential for future therapeutic applications.

A non-lipid nucleic acid delivery vector with dendritic cell tropism and stimulation.

Rationale: Nucleic acid constructs are commonly used for vaccination, immune stimulation, and gene therapy, but their use in cancer still remains limited. One of the reasons is that systemic delivery to tumor-associated antigen-presenting cells (dendritic cells and macrophages) is often inefficient, while off-target nucleic acid-sensing immune pathways can stimulate systemic immune responses. Conversely, certain carbohydrate nanoparticles with small molecule payloads have been shown to target these cells efficiently in the tumor microenvironment. Yet, nucleic acid incorporation into such carbohydrate-based nanoparticles has proven challenging. Methods: We developed a novel approach using cross-linked bis succinyl-cyclodextrin (b-s-CD) nanoparticles to efficiently deliver nucleic acids and small-molecule immune enhancer to phagocytic cells in tumor environments and lymph nodes. Our study involved incorporating these components into the nanoparticles and assessing their efficacy in activating antigen-presenting cells. Results: The multi-modality immune stimulators effectively activated antigen-presenting cells and promoted anti-tumor immunity in vivo. This was evidenced by enhanced delivery to phagocytic cells and subsequent immune response activation in tumor environments and lymph nodes. Conclusion: Here, we describe a new approach to incorporating both nucleic acids and small-molecule immune enhancers into cross-linked bis succinyl-cyclodextrin (b-s-CD) nanoparticles for efficient delivery to phagocytic cells in tumor environments and lymph nodes in vivo. These multi-modality immune stimulators can activate antigen-presenting cells and foster anti-tumor immunity. We argue that this strategy can potentially be used to enhance anti-tumor efficacy.

Prevalence, tropism, and activity of cutavirus in circulating blood lymphocytes, stool, and skin biopsy specimens of patients with cutaneous T-cell lymphoma and parapsoriasis en plaques.

A significant association has been established between a newly emerging human parvovirus, cutavirus (CuV), and cutaneous T-cell lymphoma/mycosis fungoides (CTCL/MF) and its precursor parapsoriasis en plaques (PP). CTCL is a heterogeneous group of skin malignancies of T cells, the cause of which remains unknown. This study aimed to determine the activity, spread, and cell tropism of the skin-persistent CuV. CuV DNA was detected in both skin biopsies (6/20, 30%) and peripheral blood mononuclear cells (PBMCs) (4/29, 13.8%) from 49 CTCL/MF or PP patients, while none from 33 patients with any other type of skin disease or healthy subjects harbored CuV DNA. CuV DNA persisted in the skin or PBMCs for up to 15 years, despite circulating CuV-specific IgG. Spliced CuV mRNA was expressed in skin, indicating viral activity. Also, both of two available stool samples contained encapsidated CuV genomes, suggesting that the patients excrete infectious virus into the environment. Finally, CuV was observed to target circulating and skin-resident CD4 + T cells and some skin keratinocytes and macrophages. This is especially intriguing as malignant T cells in CTCL develop from CD4 + T cells. Hence, CuV should be further investigated for the overall role it plays in the complex tumor microenvironment of CTCL/MF.

Amyloplast is involved in the MIZ1-modulated root hydrotropism.

Roots exhibit hydrotropism in response to moisture gradients, with the hydrotropism-related gene Mizu-kussei1 (MIZ1) playing a role in regulating root hydrotropism in an oblique orientation. However, the mechanisms underlying MIZ1-regulated root hydrotropism are not well understood. In this study, we employed obliquely oriented experimental systems to investigate root hydrotropism in Arabidopsis. We found that the miz1 mutant displays reduced root hydrotropism but increased root gravitropism following hydrostimulation, as compared to wild-type plants. Conversely, overexpression of AtMIZ1 leads to enhanced root hydrotropism but decreased root gravitropism following hydrostimulation, as compared to wild-type plants. Using co-immunoprecipitation followed by mass spectrometry (IP-MS), we explored proteins that interact with AtMIZ1, and we identified PGMC1 co-immunoprecipitated with MIZ1 in vivo. Furthermore, the miz1 mutant exhibited higher expression of the PGMC1 gene and increased phosphoglucomutase (PGM) activity, while AtMIZ1 overexpressors resulted in lower expression of the PGMC1 gene, reduced amyloplast amount, and reduced PGM activity in comparison to wild-type roots. In addition, different Arabidopsis natural accessions having difference in their hydrotropic response demonstrated expression level of PGMC1 was negatively correlated with hydrotropic root curvature and AtMIZ1 expression. Our results provide valuable insights into the role of amyloplast in MIZ1-regulated root hydrotropism.

Defects in the cell wall and its deposition caused by loss-of-function of three RLKs alter root hydrotropism in Arabidopsis thaliana.

Root tips can sense moisture gradients and grow into environments with higher water potential. This process is called root hydrotropism. Here, we report three closely related receptor-like kinases (RLKs) that play critical roles in root hydrotropism: ALTERED ROOT HYDROTROPIC RESPONSE 1 (ARH1), FEI1, and FEI2. Overexpression of these RLKs strongly reduce root hydrotropism, but corresponding loss-of-function mutants exhibit an increased hydrotropic response in their roots. All these RLKs show polar localization at the plasma membrane regions in root tips. The biosynthesis of the cell wall, cutin, and wax (CCW) is significantly impaired in root tips of arh1-2 fei1-C fei2-C. A series of known CCW mutants also exhibit increased root hydrotropism and reduced osmotic tolerance, similar to the characteristics of the triple mutant. Our results demonstrat that the integrity of the cell wall, cutin, and root cap wax mediate a trade-off between root hydrotropism and osmotic tolerance.

A Whole-Spine Magnetic Resonance Imaging-Based Cross-Sectional Study of the Clinicoradiological Association of Lumbosacral Transitional Vertebra with Degenerative Disc Disease, End Plate Degeneration, Low Back Pain, and Facet Tropism.

OBJECTIVE: To understand lumbosacral transitional vertebra (LSTV)-associated degenerative pathologies and their correlation to low back pain and radicular pain. METHODS: Whole-spine magnetic resonance imaging was evaluated for disc degeneration using Pfirrmann grading, end plate changes using total end plate score (TEPS), and facet tropism in patients with low back pain and radicular pain, and their association with LSTV was analyzed. RESULTS: In group 1, LSTV was seen in 15% of patients with 83% of these patients having sacralization. Disc degeneration was seen in 58%, 51%, and 63% of patients at levels C, B, and A, respectively; patients with sacralization had significant degeneration at all 3 levels. Similarly, the total end plate score and facet tropism were significantly higher in patients with sacralization. Facet tropism was observed in 31%, 40%, and 35% of patients with no -LSTV, patients with sacralization, and patients with lumbarization, respectively. In group 2, LSTV was seen in 17% of patients with sacralization accounting for 82%. Disc degeneration was seen in 44%, 36%, and 54% patients at levels C, B, and A, respectively. No significant difference was observed in the mean total end plate score between groups. Facet tropism was identified in 89% and 81% of patients with sacralization and patients with lumbarization, respectively, compared with only 19% of patients with no LSTV. CONCLUSIONS: Patients with low back pain had a higher incidence of sacralization with corresponding disc degeneration, facet tropism ,and end plate changes. In patients with radicular pain, lumbarization was associated only with facet tropism. These findings may aid clinicians in prognostication and patient counseling.

Natural Adeno-Associated Virus Serotypes and Engineered Adeno-Associated Virus Capsid Variants: Tropism Differences and Mechanistic Insights.

Today, adeno-associated virus (AAV)-based vectors are arguably the most promising in vivo gene delivery vehicles for durable therapeutic gene expression. Advances in molecular engineering, high-throughput screening platforms, and computational techniques have resulted in a toolbox of capsid variants with enhanced performance over parental serotypes. Despite their considerable promise and emerging clinical success, there are still obstacles hindering their broader use, including limited transduction capabilities, tissue/cell type-specific tropism and penetration into tissues through anatomical barriers, off-target tissue biodistribution, intracellular degradation, immune recognition, and a lack of translatability from preclinical models to clinical settings. Here, we first describe the transduction mechanisms of natural AAV serotypes and explore the current understanding of the systemic and cellular hurdles to efficient transduction. We then outline progress in developing designer AAV capsid variants, highlighting the seminal discoveries of variants which can transduce the central nervous system upon systemic administration, and, to a lesser extent, discuss the targeting of the peripheral nervous system, eye, ear, lung, liver, heart, and skeletal muscle, emphasizing their tissue and cell specificity and translational promise. In particular, we dive deeper into the molecular mechanisms behind their enhanced properties, with a focus on their engagement with host cell receptors previously inaccessible to natural AAV serotypes. Finally, we summarize the main findings of our review and discuss future directions.

The timing of HIV-1 infection of cells that persist on therapy is not strongly influenced by replication competency or cellular tropism of the provirus.

People with HIV-1 (PWH) on antiretroviral therapy (ART) can maintain undetectable virus levels, but a small pool of infected cells persists. This pool is largely comprised of defective proviruses that may produce HIV-1 proteins but are incapable of making infectious virus, with only a fraction (~10%) of these cells harboring intact viral genomes, some of which produce infectious virus following ex vivo stimulation (i.e. inducible intact proviruses). A majority of the inducible proviruses that persist on ART are formed near the time of therapy initiation. Here we compared proviral DNA (assessed here as 3' half genomes amplified from total cellular DNA) and inducible replication competent viruses in the pool of infected cells that persists during ART to determine if the original infection of these cells occurred at comparable times prior to therapy initiation. Overall, the average percent of proviruses that formed late (i.e. around the time of ART initiation, 60%) did not differ from the average percent of replication competent inducible viruses that formed late (69%), and this was also true for proviral DNA that was hypermutated (57%). Further, there was no evidence that entry into the long-lived infected cell pool was impeded by the ability to use the CXCR4 coreceptor, nor was the formation of long-lived infected cells enhanced during primary infection, when viral loads are exceptionally high. We observed that infection of cells that transitioned to be long-lived was enhanced among people with a lower nadir CD4+ T cell count. Together these data suggest that the timing of infection of cells that become long-lived is impacted more by biological processes associated with immunodeficiency before ART than the replication competency and/or cellular tropism of the infecting virus or the intactness of the provirus. Further research is needed to determine the mechanistic link between immunodeficiency and the timing of infected cells transitioning to the long-lived pool, particularly whether this is due to differences in infected cell clearance, turnover rates and/or homeostatic proliferation before and after ART.

Multichannel-optical imaging for in vivo evaluating the safety and therapeutic efficacy of stem cells in tumor model in terms of cell tropism, proliferation and NF-κB activity.

Stem cell-based cancer treatment has garnered significant attention, yet its safety and efficacy remain incompletely understood. The nuclear factor-kappa B (NF-κB) pathway, a critical signaling mechanism involved in tumor growth, angiogenesis, and invasion, serves as an essential metric for evaluating the behavior of stem cells in tumor models. Herein, we report the development of a triple-channel imaging system capable of simultaneously monitoring the tropism of stem cells towards tumors, assessing tumor proliferation, and quantifying tumor NF-κB activity. In this system, we generated a CRISPR-Cas9 gene-edited human glioblastoma cell line, GE-U87-MG, which provided a reliable readout of the proliferation and NF-κB activity of tumors by EF1α-RFLuc- and NF-κB-GLuc-based bioluminescent imaging, respectively. Additionally, near infrared-II emitting Tat-PEG-AgAuSe quantum dots were developed for tracking of stem cell tropism towards tumor. In a representative case involving human mesenchymal stem cells (hMSCs), multichannel imaging revealed no discernible effect of hMSCs on the proliferation and NF-κB activity of GE-U87-MG tumors. Moreover, hMSCs engineered to overexpress the necrosis factor-related apoptosis-inducing ligand were able to inhibit NF-κB activity and growth of GE-U87-MG in vivo. Taken together, our imaging system represents a powerful and feasible approach to evaluating the safety and therapeutic efficacy of stem cells in tumor models.

Translational Control of Alphavirus-Host Interactions: Implications in Viral Evolution, Tropism and Antiviral Response.

Alphaviruses can replicate in arthropods and in many vertebrate species including humankind, but only in vertebrate cells do infections with these viruses result in a strong inhibition of host translation and transcription. Translation shutoff by alphaviruses is a multifactorial process that involves both host- and virus-induced mechanisms, and some of them are not completely understood. Alphavirus genomes contain cis-acting elements (RNA structures and dinucleotide composition) and encode protein activities that promote the translational and transcriptional resistance to type I IFN-induced antiviral effectors. Among them, IFIT1, ZAP and PKR have played a relevant role in alphavirus evolution, since they have promoted the emergence of multiple viral evasion mechanisms at the translational level. In this review, we will discuss how the adaptations of alphaviruses to vertebrate hosts likely involved the acquisition of new features in viral mRNAs and proteins to overcome the effect of type I IFN.

Hydrotropism mechanisms and their interplay with gravitropism.

Plants partly optimize their water recruitment from the growth medium by directing root growth toward a moisture source, a phenomenon termed hydrotropism. The default mechanism of downward growth, termed gravitropism, often functions to counteract hydrotropism when the water-potential gradient deviates from the gravity vector. This review addresses the identity of the root sites in which hydrotropism-regulating factors function to attenuate gravitropism and the interplay between these various factors. In this context, the function of hormones, including auxin, abscisic acid, and cytokinins, as well as secondary messengers, calcium ions, and reactive oxygen species in the conflict between these two opposing tropisms is discussed. We have assembled the available data on the effects of various chemicals and genetic backgrounds on both gravitropism and hydrotropism, to provide an up-to-date perspective on the interactions that dictate the orientation of root tip growth. We specify the relevant open questions for future research. Broadening our understanding of root mechanisms of water recruitment holds great potential for providing advanced approaches and technologies that can improve crop plant performance under less-than-optimal conditions, in light of predicted frequent and prolonged drought periods due to global climate change.

Cardiac damage and tropism of severe acute respiratory syndrome coronavirus 2.

Until now, the World Health Organization registered over 771 million cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection worldwide, of which 6.97 million resulted in death. Virus-related cardiovascular events and pre-existing heart problems have been identified as major contributing factors to global infection-related morbidity and mortality, emphasizing the necessity for risk assessment and future prevention. In this review, we highlight cardiac manifestations that might arise from an infection with SARS-CoV-2 and provide an overview of known comorbidities that worsen the outcome. Additionally, we aim to summarize the therapeutic strategies proposed to reverse virus-associated myocardial damage, which will be further highlighted in this review, with an outlook to successful recovery and prevention.

Human metapneumovirus infection of organoid-derived human bronchial epithelium represents cell tropism and cytopathology as observed in in vivo models.

Human metapneumovirus (HMPV), a member of the Pneumoviridae family, causes upper and lower respiratory tract infections in humans. In vitro studies with HMPV have mostly been performed in monolayers of undifferentiated epithelial cells. In vivo studies in cynomolgus macaques and cotton rats have shown that ciliated epithelial cells are the main target of HMPV infection, but these observations cannot be studied in monolayer systems. Here, we established an organoid-derived bronchial culture model that allows physiologically relevant studies on HMPV. Inoculation with multiple prototype HMPV viruses and recent clinical virus isolates led to differences in replication among HMPV isolates. Prolific HMPV replication in this model caused damage to the ciliary layer, including cilia loss at advanced stages post-infection. These cytopathic effects correlated with those observed in previous in vivo studies with cynomolgus macaques. The assessment of the innate immune responses in three donors upon HMPV and RSV inoculation highlighted the importance of incorporating multiple donors to account for donor-dependent variation. In conclusion, these data indicate that the organoid-derived bronchial cell culture model resembles in vivo findings and is therefore a suitable and robust model for future HMPV studies. IMPORTANCE: Human metapneumovirus (HMPV) is one of the leading causative agents of respiratory disease in humans, with no treatment or vaccine available yet. The use of primary epithelial cultures that recapitulate the tissue morphology and biochemistry of the human airways could aid in defining more relevant targets to prevent HMPV infection. For this purpose, this study established the first primary organoid-derived bronchial culture model suitable for a broad range of HMPV isolates. These bronchial cultures were assessed for HMPV replication, cellular tropism, cytopathology, and innate immune responses, where the observations were linked to previous in vivo studies with HMPV. This study exposed an important gap in the HMPV field since extensively cell-passaged prototype HMPV B viruses did not replicate in the bronchial cultures, underpinning the need to use recently isolated viruses with a controlled passage history. These results were reproducible in three different donors, supporting this model to be suitable to study HMPV infection.

Quaternization drives spleen-to-lung tropism conversion for mRNA-loaded lipid-like nanoassemblies.

Background: As the overwhelming majority of advanced mRNA delivery systems are preferentially accumulated in the liver, there is an accelerating growth in the demand for the development of non-liver mRNA delivery platforms. Methods: In this study, we prepared cationic lipid-like nanoassemblies through a N-quaternizing strategy. Their physicochemical properties, in vitro mRNA delivery efficiency, and organ tropism in mice were investigated. Results: Introduction of quaternary ammonium groups onto lipid-like nanoassemblies not only enhances their mRNA delivery performance in vitro, but also completely alters their tropism from the spleen to the lung after intravenous administration in mice. Quaternized lipid-like nanoassemblies exhibit ultra-high specificity to the lung and are predominantly taken up by pulmonary immune cells, leading to over 95% of exogenous mRNA translation in the lungs. Such mRNA delivery carriers are stable even after more than one-year storage at ambient temperature. Conclusions: Quaternization provides an alternative method for design of new lung-targeted mRNA delivery systems without incorporation of targeting ligands, which should extend the therapeutic applicability of mRNA to lung diseases.

Vertical mother-to-infant transmission of herpes simplex virus 2 is correlated with tropism due to mutations in viral UL13.

Although neonates are commonly exposed to vaginal herpes simplex virus (HSV)-2, neonatal herpes is rare. Therefore, we analyzed paired infant and maternal HSV-2 isolates from two cases of mother-to-infant transmission to identify viral factors contributing to vertical transmission. Sixteen infant isolates with neonatal herpes and 27 genital isolates in their third trimester were included. The infant isolates were significantly more temperature-independent than the maternal isolates. Sequence comparison revealed viral UL13 protein kinase (UL13-PK) mutation in the infant isolates in both cases. In the expanded cohort, infant isolates (5/18) had significantly more UL13-PK mutations than genital isolates (1/29). Isolates within 8 days post-birth (3/4) had a significantly higher frequency of UL13-PK mutation than those after 9 days (2/14), suggesting a close association between UL13-PK mutations and vertical transmission. Elongation factor 1-delta was identified as a target of UL13-PK by proteomic analysis of UL13-PK-positive and -negative HepG2 cells. The mixed infant isolates with the intact and mutated UL13-PK conferred altered cell tropism, temperature independence adapting to fetal temperature, and better growth properties in Vero and hepatoblastoma HepG2 cells than in HSV-2 with intact and mutated UL13-PK alone, indicating that viral UL13-PK mutation is essential for vertical HSV-2 transmission.

ACE2 and TMPRSS2 distribution in the respiratory tract of different animal species and its correlation with SARS-CoV-2 tissue tropism.

A wide range of animal species show variable susceptibility to SARS-CoV-2; however, host factors associated with varied susceptibility remain to be defined. Here, we examined whether susceptibility to SARS-CoV-2 and virus tropism in different animal species are dependent on the expression and distribution of the virus receptor angiotensin-converting enzyme 2 (ACE2) and the host cell factor transmembrane serine protease 2 (TMPRSS2). We cataloged the upper and lower respiratory tract of multiple animal species and humans in a tissue-specific manner and quantitatively evaluated the distribution and abundance of ACE2 and TMPRSS2 mRNA in situ. Our results show that: (i) ACE2 and TMPRSS2 mRNA are abundant in the conduction portion of the respiratory tract, (ii) ACE2 mRNA occurs at a lower abundance compared to TMPRSS2 mRNA, (iii) co-expression of ACE2-TMPRSS2 mRNAs is highest in those species with the highest susceptibility to SARS-CoV-2 infection (i.e., cats, Syrian hamsters, and white-tailed deer), and (iv) expression of ACE2 and TMPRSS2 mRNA was not altered following SARS-CoV-2 infection. Our results demonstrate that while specific regions of the respiratory tract are enriched in ACE2 and TMPRSS2 mRNAs in different animal species, this is only a partial determinant of susceptibility to SARS-CoV-2 infection.IMPORTANCESARS-CoV-2 infects a wide array of domestic and wild animals, raising concerns regarding its evolutionary dynamics in animals and potential for spillback transmission of emerging variants to humans. Hence, SARS-CoV-2 infection in animals has significant public health relevance. Host factors determining animal susceptibility to SARS-CoV-2 are vastly unknown, and their characterization is critical to further understand susceptibility and viral dynamics in animal populations and anticipate potential spillback transmission. Here, we quantitatively assessed the distribution and abundance of the two most important host factors, angiotensin-converting enzyme 2 and transmembrane serine protease 2, in the respiratory tract of various animal species and humans. Our results demonstrate that while specific regions of the respiratory tract are enriched in these two host factors, they are only partial determinants of susceptibility. Detailed analysis of additional host factors is critical for our understanding of the underlying mechanisms governing viral susceptibility and reservoir hosts.

Semiautomatic Assessment of Facet Tropism From Lumbar Spine MRI Using Deep Learning: A Northern Finland Birth Cohort Study.

STUDY DESIGN: This is a retrospective, cross-sectional, population-based study that automatically measured the facet joint (FJ) angles from T2-weighted axial magnetic resonance imagings (MRIs) of the lumbar spine using deep learning (DL). OBJECTIVE: This work aimed to introduce a semiautomatic framework that measures the FJ angles using DL and study facet tropism (FT) in a large Finnish population-based cohort. SUMMARY OF DATA: T2-weighted axial MRIs of the lumbar spine (L3/4 through L5/S1) for (n=1288) in the NFBC1966 Finnish population-based cohort were used for this study. MATERIALS AND METHODS: A DL model was developed and trained on 430 participants' MRI images. The authors computed FJ angles from the model's prediction for each level, that is, L3/4 through L5/S1, for the male and female subgroups. Inter-rater and intrarater reliability was analyzed for 60 participants using annotations made by two radiologists and a musculoskeletal researcher. With the developed method, we examined FT in the entire NFBC1966 cohort, adopting the literature definitions of FT thresholds at 7° and 10°. The rater agreement was evaluated both for the annotations and the FJ angles computed based on the annotations. FJ asymmetry ( - was used to evaluate the agreement and correlation between the raters. Bland-Altman analysis was used to assess the agreement and systemic bias in the FJ asymmetry. The authors used the Dice score as the metric to compare the annotations between the raters. The authors evaluated the model predictions on the independent test set and compared them against the ground truth annotations. RESULTS: This model scored Dice (92.7±0.1) and intersection over union (87.1±0.2) aggregated across all the regions of interest, that is, vertebral body (VB), FJs, and posterior arch (PA). The mean FJ angles measured for the male and female subgroups were in agreement with the literature findings. Intrarater reliability was high, with a Dice score of VB (97.3), FJ (82.5), and PA (90.3). The inter-rater reliability was better between the radiologists with a Dice score of VB (96.4), FJ (75.5), and PA (85.8) than between the radiologists and the musculoskeletal researcher. The prevalence of FT was higher in the male subgroup, with L4/5 found to be the most affected region. CONCLUSION: The authors developed a DL-based framework that enabled us to study FT in a large cohort. Using the proposed method, the authors present the prevalence of FT in a Finnish population-based cohort.

Brain tropism acquisition: The spatial dynamics and evolution of a measles virus collective infectious unit that drove lethal subacute sclerosing panencephalitis.

It is increasingly appreciated that pathogens can spread as infectious units constituted by multiple, genetically diverse genomes, also called collective infectious units or genome collectives. However, genetic characterization of the spatial dynamics of collective infectious units in animal hosts is demanding, and it is rarely feasible in humans. Measles virus (MeV), whose spread in lymphatic tissues and airway epithelia relies on collective infectious units, can, in rare cases, cause subacute sclerosing panencephalitis (SSPE), a lethal human brain disease. In different SSPE cases, MeV acquisition of brain tropism has been attributed to mutations affecting either the fusion or the matrix protein, or both, but the overarching mechanism driving brain adaptation is not understood. Here we analyzed MeV RNA from several spatially distinct brain regions of an individual who succumbed to SSPE. Surprisingly, we identified two major MeV genome subpopulations present at variable frequencies in all 15 brain specimens examined. Both genome types accumulated mutations like those shown to favor receptor-independent cell-cell spread in other SSPE cases. Most infected cells carried both genome types, suggesting the possibility of genetic complementation. We cannot definitively chart the history of the spread of this virus in the brain, but several observations suggest that mutant genomes generated in the frontal cortex moved outwards as a collective and diversified. During diversification, mutations affecting the cytoplasmic tails of both viral envelope proteins emerged and fluctuated in frequency across genetic backgrounds, suggesting convergent and potentially frequency-dependent evolution for modulation of fusogenicity. We propose that a collective infectious unit drove MeV pathogenesis in this brain. Re-examination of published data suggests that similar processes may have occurred in other SSPE cases. Our studies provide a primer for analyses of the evolution of collective infectious units of other pathogens that cause lethal disease in humans.

Relationship between Facet Joint Tropism with Lumbar Disc Herniation at A Particular Motion Segment.

BACKGROUND: Lumbar disc herniation is one of the important and common causes of low back pain. There are various modifiable and non-modifiable risk factors for the development of lumbar disc herniation. Any change in the orientation or asymmetry of the facet joint i.e. facet tropism may lead to abnormal shearing stress on the intervertebral disc and may lead to development of disc herniation. METHODS: This is a cross-sectional observational study of 46 patients aged 18-40 years with clinical features of Prolapsed Intervertebral Disc and Magnetic Resonance Imaging evidence of single level prolapsed disc who presented to Tribhuvan University Teaching Hospital from December 2019 to June 2021. MRI measurement of facet tropism of normal level (L4-L5 or L5-S1) adjacent to herniated level was used for comparison. The p - value ≤ 0.05 was considered statistically significant. Overall association of tropism with lumbar disc herniation in affected and normal level combined and at each individual level was studied using McNemar Test. RESULTS: We found a highly significant association of facet tropism with lumbar disc herniation (p-value <0.001). Considering the individual levels, at L4-L5 level, the association between facet tropism and lumbar disc herniation was highly significant (p-value <0.001). However, at L5-S1 level the association was not significant (p-value <0.388). CONCLUSIONS: The results of our study show strong association between FT and lumbar disc herniation at a particular motion segment.

Prognosis impact of perineural invasion in advanced stage oral squamous cell carcinoma / Impacto do prognóstico da invasão perineural no carcinoma espinocelular de boca em estágio avançado

Apesar de pesquisas recentes mostrarem baixa sobrevida em pacientes oncológicos que tiveram invasão perineural (IPN), pouco se sabe sobre a força do IPN relacionada à sobrevida do carcinoma espinocelular (CEC) de boca e em relação a suas variáveis clínico-patológicas. Os objetivos específicos do estudo foram medir o impacto do IPN na sobrevida do CEC de boca, bem como a correlação entre as características clínico-patológicas do paciente diagnosticado com CEC de boca com o IPN em pacientes tratados cirurgicamente. Foi realizado um estudo retrospectivo envolvendo 101 pacientes submetidos ao tratamento cirúrgico com ou sem associação de terapia adjuvante entre os anos de 1994 e 2016. Todas as variáveis foram inseridas simultaneamente no modelo de cox para cada modelo de sobrevida e na tabulação cruzada para avaliar a relação do IPN com as variáveis do CEC de boca. A significância estatística para o estudo foi estabelecida em um valor de P inferior a 0,05. A variável de interesse IPN provou ser preditora de sobrevida global (HR, 3,38; IC 95%, 0,139-0,624; P = 0,004) e sobrevida específica da doença (HR, 2,95; IC 95% 0,137-0,810; P=0,019). O IPN também mostrou relação com tratamento (P = 0,011) na análise de correlação. A invasão perineural foi considerada uma variável independente na sobrevida específica e global de pacientes com CEC de boca. Outros fatores relacionados à sensibilidade da avaliação do padrão de invasão perineural no CEC de boca ainda permanecem desconhecidos(AU)

Despite recent research showing low survival in cancer patients who had perineural invasion (PNI), little is known about the strength of the PNI related to oral squamous cell carcinoma (OSCC) survival and in relation to its clinicopathological variables. The specific objectives of the study were to measure the impact of the PNI on the survival of oral SCC, as well as the correlation between the clinicopathological characteristics of the patient diagnosed with OSCC of the mouth with the PNI in surgically treated patients. A retrospective study was carried out involving 101 patients who underwent surgical treatment with or without the association of adjuvant therapy between the years 1994 and 2016. All variables were entered simultaneously in the cox model for each survival model and in the cross-tabulation to evaluate the relationship between the PNI and the OSCC by mouth variables. Statistical significance for the study was established at a P value of less than 0.05. The PNI variable of interest proved to be a predictor of overall survival (HR, 3.38; 95% CI, 0.139-0.624; P = 0.004) and disease-specific survival (HR, 2.95; 95% CI 0.137-0.810; P =0.019). The PNI also showed a relationship with treatment (P = 0.011) in the correlation analysis. Perineural invasion was considered an independent variable in the specific and overall survival of patients with OSCC. Other factors related to the sensitivity of the assessment of the perineural invasion pattern in OSCC of the mouth still remain unknown(AU)