Competitive Binding of Viral Nuclear Localization Signal Peptide and Inhibitor Ligands to Importin-α Nuclear Transport Protein.

Venezuelan equine encephalitis virus (VEEV) is a highly virulent pathogen whose nuclear localization signal (NLS) sequence from capsid protein binds to the host importin-α transport protein and blocks nuclear import. We studied the molecular mechanisms by which two small ligands, termed I1 and I2, interfere with the binding of VEEV's NLS peptide to importin-α protein. To this end, we performed all-atom replica exchange molecular dynamics simulations probing the competitive binding of the VEEV coreNLS peptide and I1 or I2 ligand to the importin-α major NLS binding site. As a reference, we used our previous simulations, which examined noncompetitive binding of the coreNLS peptide or the inhibitors to importin-α. We found that both inhibitors completely abrogate the native binding of the coreNLS peptide, forcing it to adopt a manifold of nonnative loosely bound poses within the importin-α major NLS binding site. Both inhibitors primarily destabilize the native coreNLS binding by masking its amino acids rather than competing with it for binding to importin-α. Because I2, in contrast to I1, binds off-site localizing on the edge of the major NLS binding site, it inhibits fewer coreNLS native binding interactions than I1. Structural analysis is supported by computations of the free energies of the coreNLS peptide binding to importin-α with or without competition from the inhibitors. Specifically, both inhibitors reduce the free energy gain from coreNLS binding, with I1 causing significantly larger loss than I2. To test our simulations, we performed AlphaScreen experiments measuring IC50 values for both inhibitors. Consistent with in silico results, the IC50 value for I1 was found to be lower than that for I2. We hypothesize that the inhibitory action of I1 and I2 ligands might be specific to the NLS from VEEV's capsid protein.

The subacromial bursa modulates tendon healing after rotator cuff injury in rats.

Rotator cuff injuries result in more than 500,000 surgeries annually in the United States, many of which fail. These surgeries typically involve repair of the injured tendon and removal of the subacromial bursa, a synovial-like tissue that sits between the rotator cuff and the acromion. The subacromial bursa has been implicated in rotator cuff pathogenesis and healing. Using proteomic profiling of bursa samples from nine patients with rotator cuff injury, we show that the bursa responds to injury in the underlying tendon. In a rat model of supraspinatus tenotomy, we evaluated the bursa's effect on the injured supraspinatus tendon, the uninjured infraspinatus tendon, and the underlying humeral head. The bursa protected the intact infraspinatus tendon adjacent to the injured supraspinatus tendon by maintaining its mechanical properties and protected the underlying humeral head by maintaining bone morphometry. The bursa promoted an inflammatory response in injured rat tendon, initiating expression of genes associated with wound healing, including Cox2 and Il6. These results were confirmed in rat bursa organ cultures. To evaluate the potential of the bursa as a therapeutic target, polymer microspheres loaded with dexamethasone were delivered to the intact bursae of rats after tenotomy. Dexamethasone released from the bursa reduced Il1b expression in injured rat supraspinatus tendon, suggesting that the bursa could be used for drug delivery to reduce inflammation in the healing tendon. Our findings indicate that the subacromial bursa contributes to healing in underlying tissues of the shoulder joint, suggesting that its removal during rotator cuff surgery should be reconsidered.

Adaptação dos acadêmicos de Medicina em currículo PBL e tradicional ao ensino remoto na pandemia / How medical students using either PBL or a traditional curriculum adapted to online learning during the pandemic

RESUMO Introdução: Em 2020, o mundo foi afetado pelo novo coronavírus, e isso gerou mudanças históricas em diversos setores, incluindo o da educação, que teve que se adaptar rapidamente ao formato online. Objetivo: Este estudo teve como objetivo comparar se houve uma melhor adaptação ao ensino remoto durante a pandemia de Covid-19 dos acadêmicos de Medicina que estudam em currículos PBL quando comparada a de alunos com currículos em modelo disciplinar expositivo. Método: Trata-se de um estudo transversal. Foram incluídos na pesquisa os estudantes matriculados do segundo ao quarto ano do curso de Medicina que tenham preenchido o questionário completamente e cursado pelo menos um semestre de ensino remoto durante o ano de 2020. Resultado: Houve uma diferença significativa entre as metodologias, com maior adaptação dos estudantes que utilizaram o modelo PBL em comparação aos que cursaram no modelo disciplinar expositivo durante a pandemia de Covid-19. Conclusão: Na amostra estudada, o método PBL mostrou-se superior ao método disciplinar, nos quesitos avaliados, na adaptação de estudantes de Medicina ao ensino remoto.

ABSTRACT Introduction: In 2020, the new coronavirus pandemic affected the whole world, causing historic changes in several sectors, including education, in which students were forced to quickly adapt to online learning. Objective: This study aimed to compare medical students' adaptation to remote learning during the COVID-19 pandemic depending on whether they were following a PBL curriculum or a curriculum based on an expository disciplinary model. Method: This was a cross-sectional study. The sample was composed of students enrolled in the 2nd to 4th year of the Medicine course who had fully completed the questionnaire and attended at least one semester of remote learning during 2020. Result: A significant difference was found between the students' adaptation to remote learning during the Covid-19 pandemic according to their study methodology; students using the PBL model showed better adaptation than those following an expository learning model. Conclusion: The study corroborated the results in the existing literature on the subject, which defends PBL as a better alternative for online learning.

Monoclonal Gammopathy of Renal Significance with Deposits of Infrequent Morphology: Two Case Reports of Light and Heavy Chain Deposition Disease with Atypical Presentation and Literature Review.

BACKGROUND: Monoclonal immunoglobulin deposition disease (MIDD) includes three entities: light chain deposition disease (LCDD), heavy chain deposition disease (HCDD) and light and heavy chain deposition disease (LHCDD). The renal presentation can manifest with varying degrees of proteinuria and/or nephrotic syndrome, microhematuria, and often leads to end-stage renal disease. Given the rarity of LHCDD, therapeutic approaches for this condition remain inconclusive, as clinical trials are limited. CASE PRESENTATION: We report two male patients with underlying monoclonal gammopathy of renal significance (MGRS) associated with LHCDD lesions. Both cases had non-nephrotic proteinuria, moderately impaired renal function, and normal levels of C3 and C4. Light microscopy of the renal biopsies in both patients did not show lesions of nodular glomerulosclerosis. Immunofluorescence showed a staining pattern with interrupted linear IgA-κ in patient #1 and IgA-λ in patient #2 only along the glomerular basement membrane (GBM). Electron microscopy of patient #1 revealed electrodense deposits in the subendothelial and mesangial areas only along the GBM. DISCUSSION: In this case series, we discuss the clinical, analytical, and histopathological findings of two rare cases of LHCDD. Both patients exhibited IgA monoclonality and were diagnosed with monoclonal gammopathy of undetermined significance (MGUS) by the hematology department at the time of renal biopsy. Treatment with steroids and cytotoxic agents targeting the clone cells responsible for the deposition disease resulted in a favorable renal and hematologic response.

The Posterior Cranial Vertical Line: A Novel Radiographic Marker for Classifying Global Sagittal Alignment.

OBJECTIVE: To define a novel radiographic measurement, the posterior cranial vertical line (PCVL), in an asymptomatic adult population to better understand global sagittal alignment. METHODS: We performed a multicenter retrospective review of prospectively collected radiographic data on asymptomatic volunteers aged 20-79. The PCVL is a vertical plumb line drawn from the posterior-most aspect of the occiput. The horizontal distances of the PCVL to the thoracic apex (TA), posterior sagittal vertical line (PSVL, posterosuperior endplate of S1), femoral head center, and tibial plafond were measured. Classification was either grade 1 (PCVL posterior to TA and PSVL), grade 2 (PCVL anterior to TA and posterior to PSVL), or grade 3 (PCVL anterior to TA and PSVL). RESULTS: Three hundred thirty-four asymptomatic patients were evaluated with a mean age of 41 years. Eighty-three percent of subjects were PCVL grade 1, 15% were grade 2, and 3% were grade 3. Increasing PCVL grade was associated with increased age (p < 0.001), C7-S1 sagittal vertical axis (SVA) (p < 0.001), C2-7 SVA (p < 0.001). Additionally, it was associated with decreased SS (p = 0.045), increased PT (p < 0.001), and increased knee flexion (p < 0.001). CONCLUSION: The PCVL is a radiographic marker of global sagittal alignment that is simple to implement and interpret. Increasing PCVL grade was significantly associated with expected changes and compensatory mechanisms in the aging population. Most importantly, it incorporates cervical alignment parameters such as C2-7 SVA. The PCVL defines global sagittal alignment in adult volunteers and naturally distributes into 3 grades, with only 3% being grade 3 where the PCVL lies anterior to the TA and PSVL.

Binding of viral nuclear localization signal peptides to importin-α nuclear transport protein.

Using all-atom replica-exchange molecular dynamics simulations, we mapped the mechanisms of binding of the nuclear localization signal (NLS) sequence from Venezuelan equine encephalitis virus (VEEV) capsid protein to importin-α (impα) transport protein. Our objective was to identify the VEEV NLS sequence fragment that confers native, experimentally resolved binding to impα as well as to study associated binding energetics and conformational ensembles. The two selected VEEV NLS peptide fragments, KKPK and KKPKKE, show strikingly different binding mechanisms. The minNLS peptide KKPK binds non-natively and nonspecifically by adopting five diverse conformational clusters with low similarity to the x-ray structure 3VE6 of NLS-impα complex. Despite the prevalence of non-native interactions, the minNLS peptide still largely binds to the impα major NLS binding site. In contrast, the coreNLS peptide KKPKKE binds specifically and natively, adopting a largely homogeneous binding ensemble with a dominant, highly native-like conformational cluster. The coreNLS peptide retains most of native binding interactions, including π-cation contacts and a tryptophan cage. While KKPK binding is governed by a complex multistate free energy landscape featuring transitions between multiple binding poses, the coreNLS peptide free energy map is simple, exhibiting a single dominant native-like bound basin. We argue that the origin of the coreNLS peptide binding specificity is several electrostatic interactions formed by the two C-terminal amino acids, Lys10 and Glu11, with impα. The coreNLS sequence is then sufficient for native binding, but none of the amino acids flanking minNLS, including Lys10 and Glu11, are strictly necessary for the native pose. Our analyses indicate that the VEEV coreNLS sequence is virtually unique among human and viral proteins interacting with impα making it a potential target for VEEV-specific inhibitors.

Can Free Energy Perturbation Simulations Coupled with Replica-Exchange Molecular Dynamics Study Ligands with Distributed Binding Sites?

Free energy perturbation coupled with replica exchange with solute tempering (FEP/REST) offers a rigorous approach to compute relative free energy changes for ligands. To determine the applicability of FEP/REST for the ligands with distributed binding poses, we considered two alchemical transformations involving three putative inhibitors I0, I1, and I2 of the Venezuelan equine encephalitis virus nuclear localization signal sequence binding to the importin-α (impα) transporter protein. I0 → I1 and I0 → I2 transformations, respectively, increase or decrease the polarity of the parent molecule. Our objective was three-fold─(i) to verify FEP/REST technical performance and convergence, (ii) to estimate changes in binding free energy ΔΔG, and (iii) to determine the utility of FEP/REST simulations for conformational binding analysis. Our results are as follows. First, our FEP/REST implementation properly follows FEP/REST formalism and produces converged ΔΔG estimates. Due to ligand inherent unbinding, the better FEP/REST strategy lies in performing multiple independent trajectories rather than extending their length. Second, I0 → I1 and I0 → I2 transformations result in overall minor changes in inhibitor binding free energy, slightly strengthening the affinity of I1 and weakening that of I2. Electrostatic interactions dominate binding interactions, determining the enthalpic changes. The two transformations cause opposite entropic changes, which ultimately govern binding affinities. Importantly, we confirm the validity of FEP/REST free energy estimates by comparing them with our previous REST simulations, directly probing binding of three ligands to impα. Third, we established that FEP/REST simulations can sample binding ensembles of ligands. Thus, FEP/REST can be applied (i) to study the energetics of the ligand binding without defined poses and showing minor differences in affinities |ΔΔG| ≲ 0.5 kcal/mol and (ii) to collect ligand binding conformational ensembles.

The subacromial bursa is a key regulator of the rotator cuff and a new therapeutic target for improving repair.

Rotator cuff injuries result in over 500,000 surgeries performed annually, an alarmingly high number of which fail. These procedures typically involve repair of the injured tendon and removal of the subacromial bursa. However, recent identification of a resident population of mesenchymal stem cells and inflammatory responsiveness of the bursa to tendinopathy indicate an unexplored biological role of the bursa in the context of rotator cuff disease. Therefore, we aimed to understand the clinical relevance of bursa-tendon crosstalk, characterize the biologic role of the bursa within the shoulder, and test the therapeutic potential for targeting the bursa. Proteomic profiling of patient bursa and tendon samples demonstrated that the bursa is activated by tendon injury. Using a rat to model rotator cuff injury and repair, tenotomy-activated bursa protected the intact tendon adjacent to the injured tendon and maintained the morphology of the underlying bone. The bursa also promoted an early inflammatory response in the injured tendon, initiating key players in wound healing. In vivo results were supported by targeted organ culture studies of the bursa. To examine the potential to therapeutically target the bursa, dexamethasone was delivered to the bursa, prompting a shift in cellular signaling towards resolution of inflammation in the healing tendon. In conclusion, contrary to current clinical practice, the bursa should be retained to the greatest extent possible and provides a new therapeutically target for improving tendon healing outcomes. One Sentence Summary: The subacromial bursa is activated by rotator cuff injury and regulates the paracrine environment of the shoulder to maintain the properties of the underlying tendon and bone.

Spectroscopic insight on impact of environment on natural photoprotectants.

Biomimicry has become a key player in researching new materials for a whole range of applications. In this study, we have taken a crude extract from the red algae Palmaria palmata containing mycosporine-like amino acids - a photoprotective family of molecules. We have applied the crude extract onto a surface to assess if photoprotection, and more broadly, light-to-heat conversion, is retained; we found it is. Considering sunscreens as a specific application, we have performed transmission and reflection terahertz spectroscopy of the extract and glycerol to demonstrate how one can monitor stability in real-world applications.

Methods for Biophysical Characterization of SznF, a Member of the Heme-Oxygenase-Like Diiron Oxidase/Oxygenase Superfamily.

Nonheme diiron enzymes harness the chemical potential of oxygen to catalyze challenging reactions in biology. In their resting state, these enzymes have a diferrous cofactor that is coordinated by histidine and carboxylate ligands. Upon exposure to oxygen, the cofactor oxidizes to its diferric state forming a peroxo- adduct, capable of catalyzing a wide range of oxidative chemistries such as desaturation and heteroatom oxidation. Despite their versatility and prowess, an emerging subset of nonheme diiron enzymes has inherent cofactor instability making them resistant to structural characterization. This feature is widespread among members of the heme-oxygenase-like diiron oxidase/oxygenase (HDO) superfamily. HDOs have a flexible core structure that remodels upon metal binding. Although ~9600 HDOs have been unearthed, few have undergone functional characterization to date. In this chapter, we describe the methods that have been used to characterize the HDO N-oxygenase, SznF. We demonstrate the overexpression and purification of apo-SznF and methodology specifically designed to aid in obtaining an X-ray structure of holo-SznF. We also describe the characterization of the transient SznF-peroxo-Fe(III)2 complex by stopped-flow absorption and Mössbauer spectroscopies. These studies provide the framework for the characterization of new members of the HDO superfamily.

Binding of Venezuelan Equine Encephalitis Virus Inhibitors to Importin-α Receptors Explored with All-Atom Replica Exchange Molecular Dynamics.

Although Venezuelan equine encephalitis virus (VEEV) is a life-threatening pathogen with a capacity for epidemic outbreaks, there are no FDA-approved VEEV antivirals for humans. VEEV cytotoxicity is partially attributed to the formation of a tetrameric complex between the VEEV capsid protein, the nuclear import proteins importin-α and importin-ß, and the nuclear export protein CRM1, which together block trafficking through the nuclear pore complex. Experimental studies have identified small molecules from the CL6662 scaffold as potential inhibitors of the viral nuclear localization signal (NLS) sequence binding to importin-α. However, little is known about the molecular mechanism of CL6662 inhibition. To address this issue, we employed all-atom replica exchange molecular dynamics simulations to probe, in atomistic detail, the binding mechanism of CL6662 ligands to importin-α. Three ligands, including G281-1485 and two congeners with varying hydrophobicities, were considered. We investigated the distribution of ligand binding poses, their locations, and ligand specificities measured by the strength of binding interactions. We found that G281-1485 binds nonspecifically without forming well-defined binding poses throughout the NLS binding site. Binding of the less hydrophobic congener becomes strongly on-target with respect to the NLS binding site but remains nonspecific. However, a more hydrophobic congener is a strongly specific binder and the only ligand out of three to form a well-defined binding pose, while partially overlapping with the NLS binding site. On the basis of free energy estimates, we argue that all three ligands weakly compete with the viral NLS sequence for binding to importin-α in an apparent compromise to preserve host NLS binding. We further show that all-atom replica exchange binding simulations are a viable tool for studying ligands binding nonspecifically without forming well-defined binding poses.

Visão de estudantes de medicina sobre os resultados da pandemia de Covid-19 no currículo paralelo / Medical students' perspective about the results of the Covid-19 pandemic in the parallel curriculum / Visión de estudiantes de medicina sobre los resultados de la pandemia de Covid-19 en el curriculum paralelo

A pandemia de Covid-19 impactou significativamente a educação médica, em especial o currículo paralelo, que engloba diversas atividades extracurriculares, tais quais: ligas acadêmicas, estágios, projeto de extensão, iniciação científica, monitoria e disciplinas optativas. Este estudo pretende analisar o resultado da pandemia de Covid-19 sobre o currículo paralelo sob a ótica de acadêmicos de Medicina. Trata-se de um estudo exploratório-descritivo, com recorte transversal, por meio de questionário online via Google Forms® com perguntas na escala tipo Likert. A amostra foi composta por 340 estudantes de Medicina, cursando do 4º ao 12º período, de Curitiba, Paraná. A modalidade onlinefacilitou a submissão de trabalhos científicos, bem como a acessibilidade a eventos médicos, que obtiveram maior adesão dentre as atividades avaliadas. Destaca-se a participação em pesquisas científicas, em especial pelos alunos do ciclo básico/clínico. Logo, a maioria dos participantes concordam que existem adaptações a serem mantidas no período pós pandemia.

The Covid-19 pandemic has significantly impacted medical education, especially the parallel curriculum, which encompasses several extracurricular activities, such as academic leagues, internships, extension projects, undergraduate research projects, teaching assistance, and elective courses. This study aims at analyzing the result of the Covid-19 pandemic on the parallel curriculum from the perspective of medical students. This is an exploratory-descriptive, cross-sectional study, using an online questionnaire via Google Forms® with Likert-type scale questions. The sample consisted of 340 Medicine students, from the 4th to the 12th terms, from Curitiba, Paraná. The online modality facilitated the submission of scientific papers, as well as the accessibility to medical events, which had the highest adherence among the evaluated activities. Participation in scientific research stands out, especially for students in the basic/clinical cycle. Therefore, most participants agree that there are adaptations to be maintained in the post-pandemic period.

La pandemia de Covid-19 impactó la educación médica, especialmente en el currículo paralelo, que incluye actividades extracurriculares, como: ligas académicas, pasantías, proyectos de extensión, iniciación científica, seguimiento y optativas. Este estudio pretende analizar el resultado de la pandemia de Covid-19 en el currículo paralelo desde la perspectiva de los estudiantes de medicina. Se trata de un estudio exploratorio-descriptivo, transversal, utilizando un cuestionario online a través de Google Forms® con preguntas en escala tipo Likert. La muestra se compone por 340 estudiantes de medicina del 4º al 12º período, en Curitiba, Paraná. La modalidad online facilitó el envío de trabajos científicos y la accesibilidad a eventos médicos, ue obtuvo mayor adhesión entre las actividades evaluadas. Cabe destacar la participación en la investigación científica, especialmente de los estudiantes del ciclo básico/clínico. Así, la mayoría de los participantes está de acuerdo de que hay adaptaciones que deben mantenerse en el período posterior a la pandemia.

A Case Report of Tuberous Sclerosis and Autosomal Dominant Polycystic Kidney Disease in the Era of Tolvaptan.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) may coexist with other genetic disorders, such as tuberous sclerosis, when deletion in TSC2/PKD1 genes occurs. Recently, the effect of tolvaptan has been explored in ADPKD patients alone, but its safety and efficacy on TSC2/PKD1 contiguous gene syndrome are unknown. CASE PRESENTATION: This report describes the case of an asymptomatic patient with TSC2/PKD1 contiguous gene syndrome that fulfills the imaging criteria for initiating the treatment with tolvaptan. After twelve months, the patient did not exhibit severe adverse effects and blood pressure control improved. CONCLUSION: In this TSC2/PKD1 contiguous gene syndrome single case report, tolvaptan was safe and well-tolerated. More extensive experimental studies are needed to deeply understand the therapeutic implications of vasopressin V2-receptor inhibition in the TSC2/PKD1 contiguous gene syndrome patients.

Addressing pollination deficits in orchard crops through habitat management for wild pollinators.

There is increasing evidence that farmers in many areas are achieving below maximum yields due to insufficient pollination. Practical and effective approaches are needed to maintain wild pollinator populations within agroecosystems so they can deliver critical pollination services that underpin crop production. We established nesting and wildflower habitat interventions in 24 UK apple orchards and measured effects on flower-visiting insects and the pollination they provide, exploring how this was affected by landscape context. We quantified the extent of pollination deficits and assessed whether the management of wild pollinators can reduce deficits and deliver improved outcomes for growers over 3 years. Wildflower interventions increased solitary bee numbers visiting apple flowers by over 20%, but there was no effect of nesting interventions. Other pollinator groups were influenced by both local and landscape-scale factors, with bumblebees and hoverflies responding to the relative proportion of semi-natural habitat at larger spatial scales (1000 m), while honeybees and other flies responded at 500 m or less. By improving fruit number and quality, pollinators contributed more than £16 k per hectare. However, deficits (where maximum potential was not being reached due to a lack of pollination) were recorded and the extent of these varied across orchards, and from year to year, with a 22% deficit in output in the worst (equivalent to ~£14 k/ha) compared to less than 3% (equivalent to ~£2 k/ha) in the best year. Although no direct effect of our habitat interventions on deficits in gross output was observed, initial fruit set and seed set deficits were reduced by abundant bumblebees, and orchards with a greater abundance of solitary bees saw lower deficits in fruit size. The abundance of pollinators in apple orchards is influenced by different local and landscape factors that interact and vary between years. Consequently, pollination, and the extent of economic output deficits, also vary between orchards and years. We highlight how approaches, including establishing wildflower areas and optimizing the ratio of cropped and non-cropped habitats can increase the abundance of key apple pollinators and improve outcomes for growers.

Rerupture and wound complications following Achilles tendon repair: A systematic review.

Despite the relatively high frequency of Achilles ruptures, there is no general consensus on the optimal treatment method. A general trend toward more patients being treated nonoperatively has emerged recently with the advent of functional rehabilitation. However, much of the recent data on this subject has been highly variable. This systematic review focused on Achilles tendon rupture (ATR) treatment outcomes, with a focus on rerupture and complication rates. This systematic review specifically focused on articles regarding ATR treatment that also included rerupture and complication rates. Treatments were divided into three categories: open minimally invasive, open standard, and nonoperative. Bivariate analyses were performed to compare complication and rerupture rates among pairs of treatment options, as well as between early weight bearing versus immobilization. There was significantly higher complications for minimally invasive compared to nonoperative treatment (risk ratio [RR] = 4.4154; p < 0.05), lower complication rates for minimally invasive compared to open treatment (RR = 0.3231; p < 0.05), and higher complications for open standard compared to nonoperative treatment (RR = 5.6350; p < 0.001). There were significantly lower rerupture rates in minimally invasive compared to nonoperative treatment (RR = 0.4085; p < 0.001), a significantly lower rerupture rate in nonoperative treatment compared to open treatment (RR = 0.2282; p < 0.001), and no significant difference in rerupture rates when comparing minimally invasive to open standard treatment. We found that operative treatment is associated with fewer reruptures and more complications than a nonoperative approach. Minimally invasive surgery appears to be associated with a lower rate of complications than open operative treatment.

Advances and challenges of CAR T therapy and suitability of animal models (Review).

Chimeric antigen receptors (CARs) recently gained momentum in cancer treatment due to their ability to promote T-cell mediated responses to a specific tumor-associated antigen. CARs are part of the adoptive cell transfer (ACT) strategies that utilize patients' T lymphocytes, genetically engineered to kill cancer cells. However, despite the therapy's success against blood-related malignancies, treating solid tumors has not reached its fullest potential yet. The reasons include the complex suppressive tumor microenvironment, mutations on cancer cells' target receptors, lethal side-effects, restricted trafficking into the tumor, suboptimal persistence in vivo and the lack of animal models that faithfully resemble human tumor's immunological responses. Currently, rodent models are used to investigate the safety and efficacy of CAR therapies. However, these models are limited in representing the human disease faithfully, fail to predict the adverse treatment events and overestimate the efficacy of the therapy. On the other hand, spontaneously developed tumors in dogs are more suited in CAR research and their efficacy has been demonstrated in a number of diseases, including lymphoma, osteosarcoma and mammary tumors. The present review discusses the design and evolution of CARs, challenges of CAR in solid tumors, human and canine clinical trials and advantages of the canine model.

Simulated and Experimental Verification for a Terahertz Specific Finite Rate of Innovation Signal Processing Method.

Recently, finite rate of innovation methods have been successfully applied to achieve low sampling rates in many areas, such as for ultrasound and radio signals. However, to the best of our knowledge, there are no journal publications applying this to real terahertz signals. In this work, we mathematically describe a finite rate of innovation method applied specifically to terahertz signals both experimentally and in simulation. To demonstrate our method, we applied it to randomized simulated signals with and without the presence of noise and to simple experimental measurements. We found excellent agreement between the simulated signals and those recreated based on results from our method, with this success also being replicated experimentally. These results were obtained at relatively low sampling rates, compared to standard methods, which is a key advantage to using a finite rate of innovation method as it allows for faster data acquisition and signal processing.

Structure-Activity Relationship of Carbon Nitride Dots in Inhibiting Tau Aggregation.

Due to the numerous failed clinical trials of anti-amyloid drugs, microtubule associated protein tau (MAPT) now stands out as one of the most promising targets for AD therapy. In this study, we report for the first time the structure-dependent MAPT aggregation inhibition of carbon nitride dots (CNDs). CNDs have exhibited great promise as a potential treatment of Alzheimer's disease (AD) by inhibiting the aggregation of MAPT. In order to elucidate its structure-activity relationship, CNDs were separated via column chromatography and five fractions with different structures were obtained that were characterized by multiple spectroscopy methods. The increase of surface hydrophilic functional groups is consistent with the increase of polarity from fraction 1 to 5. Particle sizes (1-2 nm) and zeta potentials (~-20 mV) are similar among five fractions. With the increase of polarity from fraction 1 to 5, their MAPT aggregation inhibition capacity was weakened. This suggests hydrophobic interactions between CNDs and MAPT, validated via molecular dynamics simulations. With a zebrafish blood-brain barrier (BBB) model, CNDs were observed to cross the BBB through passive diffusion. CNDs were also found to inhibit the generation of multiple reactive oxygen species, which is an important contributor to AD pathogenesis.