Camptothesome-based combination nanotherapeutic regimen for improved colorectal cancer immunochemotherapy.

Camptothesome is a sphingomyelin-conjugated camptothecin (SM-CSS-CPT) nanovesicle that fortified the therapeutic delivery of CPT in diverse cancer types. To mitigate the Camptothesome-induced IDO1 negative feedback mechanism, we had co-encapsulated, indoximod (IND, IDO1 inhibitor) into Camptothesome using doxorubicin-derived IND (DOX-IND). To maximize the therapeutic potential of DOX-IND/Camptothesome, herein, we first dissected the synergistic drug ratio (DOX-IND/SM-CSS-CPT) via systematical in vitro screening. DOX-IND/Camptothesome with optimal drug ratio synchronized in vivo drug delivery with significantly higher tumor uptake compared to free drugs. This optimum DOX-IND/Camptothesome outperformed the combination of Camptothesome, Doxil and IND or other IDO1 inhibitors (BMS-986205 or epacadostat) in treating mice bearing late-stage MC38 tumors, and combination with immune checkpoint blockade (ICB) enabled it to eradicate 60 % of large tumors. Further, this optimized co-delivery Camptothesome beat Folfox and Folfiri, two first-line combination chemotherapies for colorectal cancer in antitumor efficacy and exhibited no side effects as compared to the severe systemic toxicities associated with Folfox and Folfiri. Finally, we demonstrated that the synergistic DOX-IND/Camptothesome was superior to the combined use of Onivyde + Doxil + IND in curbing the advanced orthotopic CT26-Luc tumors and eliminated 40 % tumors with complete metastasis remission when cooperated with ICB, eliciting stronger anti-CRC immune responses and greater reversal of immunosuppression. These results corroborated that with precise optimal synergistic drug ratio, the therapeutic potential of DOX-IND/Camptothesome can be fully unleased, which warrants further clinical investigation to benefit the cancer patients.

Connectivity and molecular profiles of Foxp2- and Dbx1-lineage neurons in the accessory olfactory bulb and medial amygdala.

In terrestrial vertebrates, the olfactory system is divided into main (MOS) and accessory (AOS) components that process both volatile and nonvolatile cues to generate appropriate behavioral responses. While much is known regarding the molecular diversity of neurons that comprise the MOS, less is known about the AOS. Here, focusing on the vomeronasal organ (VNO), the accessory olfactory bulb (AOB), and the medial amygdala (MeA), we reveal that populations of neurons in the AOS can be molecularly subdivided based on their ongoing or prior expression of the transcription factors Foxp2 or Dbx1, which delineate separate populations of GABAergic output neurons in the MeA. We show that a majority of AOB neurons that project directly to the MeA are of the Foxp2 lineage. Using single-neuron patch-clamp electrophysiology, we further reveal that in addition to sex-specific differences across lineage, the frequency of excitatory input to MeA Dbx1- and Foxp2-lineage neurons differs between sexes. Together, this work uncovers a novel molecular diversity of AOS neurons, and lineage and sex differences in patterns of connectivity.

Sphingomyelin-derived nanovesicles for the delivery of the IDO1 inhibitor epacadostat enhance metastatic and post-surgical melanoma immunotherapy.

Epacadostat (EPA), the most advanced IDO1 inhibitor, in combination with PD-1 checkpoint inhibitor, has failed in a recent Phase III clinical trial for treating metastatic melanoma. Here we report an EPA nanovesicle therapeutic platform (Epacasome) based on chemically attaching EPA to sphingomyelin via an oxime-ester bond highly responsive to hydrolase cleavage. Via clathrin-mediated endocytosis, Epacasome displays higher cellular uptake and enhances IDO1 inhibition and T cell proliferation compared to free EPA. Epacasome shows improved pharmacokinetics and tumour accumulation with efficient intratumoural drug release and deep tumour penetration. Additionally, it outperforms free EPA for anticancer efficacy, potentiating PD-1 blockade with boosted cytotoxic T lymphocytes (CTLs) and reduced regulatory T cells and myeloid-derived suppressor cells responses in a B16-F10 melanoma model in female mice. By co-encapsulating immunogenic dacarbazine, Epacasome further enhances anti-tumor effects and immune responses through the upregulation of NKG2D-mediated CTLs and natural killer cells responses particularly when combined with the PD-1 inhibitor in the late-stage metastatic B16-F10-Luc2 model in female mice. Furthermore, this combination prevents tumour recurrence and prolongs mouse survival in a clinically relevant, post-surgical melanoma model in female mice. Epacasome demonstrates potential to synergize with PD-1 blockade for improved response to melanoma immunotherapy.

Sleep disordered breathing in infants identified through newborn screening with spinal muscular atrophy.

BACKGROUND: Spinal muscular atrophy (SMA) is a genetic disorder that may result in neuromuscular weakness and respiratory insufficiency. Gene replacement therapy has changed the trajectory of this condition, but long-term outcomes related to sleep disordered breathing are not known. METHODS: This was a retrospective review of infants with SMA identified via newborn screening who subsequently received onasemnogene abeparvovec at the Hospital for Sick Children (Ontario, Canada). Polysomnograms were conducted at the time of confirmed diagnosis as well as regularly thereafter. RESULTS: Eleven children (4 female) were identified via newborn screen (7 with 2 copies of the SMN2 gene and 4 with 3 copies of the SMN2 gene) and received onasemnogene abeparvovec at a median age of 3.6 weeks. All eleven infants met criteria for sleep disordered breathing based on their first completed polysomnograms but improved over time. Three infants required respiratory technology, including a premature infant who was prescribed nocturnal supplemental oxygen therapy for central sleep apnea and two symptomatic infants with neuromuscular weakness who required nocturnal noninvasive ventilation. We did not find a correlation between motor scores and polysomnogram parameters. CONCLUSION: Children treated with onasemnogene abeparvovec have reduced sleep disordered breathing over time. Polysomnograms revealed abnormal parameters in all children, but the clinical significance of these findings was unclear for children who were asymptomatic for sleep disordered breathing or neuromuscular weakness. These results highlight the need to evaluate both motor scores and respiratory symptoms to ensure a holistic evaluation of clinical status.

Does Institutional Quality Matter for Foreign Direct Investment and Human Development?

This study examines the relationship between foreign direct investment (FDI), institutional quality and human development) in host countries from 2002 to 2019, using the Human Development Index [HDI] as the measure of human development. This study utilized a panel dataset of 143 countries, including both developed and developing economies, over a 17-year period. Additionally, the study employed a GMM (generalized method of moments) estimator to address unobservable heterogeneity and simultaneity. This study reveals a significant positive relationship between FDI and human development, with a stronger effect observed in developing countries compared to in developed countries. Notably, the impact of FDI-HDI nexus is larger in countries with moderately high-quality institutions, irrespective of their income level. Furthermore, good governance plays a crucial role in enhancing human development, as developing economies with high governance quality experience a greater impact of FDI on HDI compared to other countries. The findings of this study suggest that attracting FDI can be beneficial for enhancing the HDI, especially in developing countries. Additionally, the study highlights governance as a moderating factor in the relationship between FDI and HDI. Improving governance quality can enhance the positive impact of FDI on human development in host countries, especially in developing countries.

Inequality in electricity consumption and economic growth: Evidence from a small area estimation study.

Our study uses a small area estimation method to estimate the average and inequality of per capita kWh consumption for small areas in Vietnam. It shows evidence of a large spatial heterogeneity in the electric power consumption between districts and provinces in Vietnam. Households in the mountains and highlands consumed remarkably less electricity than those in the delta and coastal areas. Notably, we find a U-shaped relationship between the inequality of electricity consumption and economic levels in Vietnam. In poor districts and provinces, there is very high inequality in electricity consumption. Inequality is lower in middle-income districts and provinces.

JAG1 Intracellular Domain Enhances AR Expression and Signaling and Promotes Stem-like Properties in Prostate Cancer Cells.

JAG1 expression is upregulated in high-grade metastatic prostate carcinomas and associated with poor disease-free survival of patients with prostate cancer. Intriguingly, all JAG1-positive prostate carcinomas express JICD although JICD function in prostate cancer (PC) cells is poorly understood. In this study, we found that JICD overexpression increased the expression levels of AR, especially AR-Vs, in PC cell lines and significantly enhanced androgen-independent and androgen-dependent function of ARs. Interestingly, JICD overexpression upregulated the expression of the PCSC marker CD133 in PC cells as the expression of self-renewal markers; namely, NANOG and OCT3/4 increased. In addition, JICD overexpression highly increased the expression of anti-apoptotic BCL-XL protein, while it little affected the expression of apoptotic BIM protein. In 3D cell culture assays, the spheres formed by JICD-overexpressing PC subline cells (C4-2 and CWR22Rv1) were larger than those formed by control (EV) subline cells with undifferentiated morphology. Although JICD overexpression caused quiescence in cell proliferation, it activated the expression of components in PCSC-related signaling pathways, increased PC cell mobility, and promoted in vivo xenograft mouse tumorigenesis. Therefore, JICD may play a crucial role in enhancing androgen independence and promoting stem-like properties in PC cells and should be considered a novel target for CRPC and PCSC diagnostic therapy.

An Analysis of the Spatiotemporal Characteristics and Diversity of Grain Production Resource Utilization Efficiency under the Constraint of Carbon Emissions: Evidence from Major Grain-Producing Areas in China.

As the most important driving force for ensuring the effective supply of grain in the country, the production stability of the major grain-producing areas directly concerns the national security of China. In this paper, considering the "water-soil-energy-carbon" correlation, water, soil and energy resource factors, and carbon emission constraints were included in an index system, and the global common frontier boundary three-stage super-efficient EBM-GML model was used to measure the grain production resource utilization efficiency of the major grain-producing areas in China from 2000 to 2019. This paper also analyzed the static and dynamic spatiotemporal characteristics and the restrictions of utilization efficiency. The results showed that, under the measurement of the traditional data envelopment analysis model, the grain production resource utilization efficiency in the major producing areas is relatively high, but there is still room to improve by more than 20%, and grain production still has enormous growth potential. After excluding external environmental and random factors, it was found that the utilization efficiency of grain production resources in the major producing areas decreased, and the efficiency and ranking of provinces changed significantly. External factors inhibit pure technical efficiency and expand the scale efficiency. The utilization efficiency of Northeast China was much higher than that of the Huang-Huai-Hai region and the middle and upper reaches of the Yangtze River region, and its grain production resource allocation management had obvious advantages. The total factor productivity index of food production resources showed an upward trend as a whole, and its change was affected by both technological efficiency and technological progress, of which technological progress had the greater impact. Therefore, reducing the differences in the external environment of different regions while making adjustments in accordance with their own potential is an effective way to further improve the utilization efficiency of food production resources.

Simultaneous Determination of Paracetamol, Ibuprofen, and Caffeine in Tablets by Molecular Absorption Spectroscopy Combined with Classical Least Square Method.

In this paper, the classical least-squares (CLS) method with molecular absorption spectrophotometric measurement was used to determine simultaneously paracetamol (PAR), ibuprofen (IBU), and caffeine (CAF) in tablets. The absorbance spectra of the standard solutions and samples were measured over a wavelength from 220 to 300 nm with a 0.5 nm step. The concentration of PAR, IBU, and CAF in the sample solutions was calculated by using Visual Basic for Applications (VBA) and a program called CLS-Excel written in Microsoft Excel 2016. The method and the CLS-Excel program were tested on mixed standard laboratory samples with different PAR, IBU, and CAF concentration ratios, and they showed only small errors and a satisfying repeatability. An analytical procedure for tablets containing PAR, IBU, and CAF was developed. The reliability of the procedure was proved via the recovery and repeatability of the analysis results with an actual tablet sample and by comparing the mean contents of active substances in the tablets obtained from the analytical procedure with the HPLC method. The procedure is simple with a reduced cost compared with the HPLC standard method.

Synthesis and Applications of Nitrogen-Containing Heterocycles as Antiviral Agents.

Viruses have been a long-term source of infectious diseases that can lead to large-scale infections and massive deaths. Especially with the recent highly contagious coronavirus (COVID-19), antiviral drugs were developed nonstop to deal with the emergence of new viruses and subject to drug resistance. Nitrogen-containing heterocycles have compatible structures and properties with exceptional biological activity for the drug design of antiviral agents. They provided a broad spectrum of interference against viral infection at various stages, from blocking early viral entry to disrupting the viral genome replication process by targeting different enzymes and proteins of viruses. This review focused on the synthesis and application of antiviral agents derived from various nitrogen-containing heterocycles, such as indole, pyrrole, pyrimidine, pyrazole, and quinoline, within the last ten years. The synthesized scaffolds target HIV, HCV/HBV, VZV/HSV, SARS-CoV, COVID-19, and influenza viruses.

TR3 Enhances AR Variant Production and Transactivation, Promoting Androgen Independence of Prostate Cancer Cells.

The pro-oncogenic function of TR3, an orphan nuclear receptor, has been reported in prostate cancer. However, the roles of TR3 in androgen receptor (AR) expression and signaling in prostate cancer cells are poorly understood. Database analysis revealed that TR3 expression level is elevated in prostate tumors, and is positively, although weakly, correlated with that of AR. TR3 overexpression increased the production of AR splice variants in addition to general upregulation of AR expression. TR3 interacted with some spliceosomal complex components and AR precursor mRNA, altering the splice junction rates between exons. TR3 also enhanced androgen-independent AR function. Furthermore, TR3 overexpression increased cell proliferation and mobility of AR-positive prostate cancer cells and stimulated tumorigenesis of androgen-independent prostate cancer cells in mouse xenograft models. This is the first study to report that TR3 is a multifunctional regulator of AR signaling in prostate cancer cells. TR3 alters AR expression, splicing process, and activity in prostate cancer cells, increasing the androgen independence of AR signaling. Therefore, TR3 may play a crucial role in the progression of prostate cancer to an advanced castration-resistant form.

The Very First Modification of Pleuromutilin and Lefamulin by Photoinitiated Radical Addition Reactions-Synthesis and Antibacterial Studies.

Pleuromutilin is a fungal diterpene natural product with antimicrobial properties, semisynthetic derivatives of which are used in veterinary and human medicine. The development of bacterial resistance to pleuromutilins is known to be very slow, which makes the tricyclic diterpene skeleton of pleuromutilin a very attractive starting structure for the development of new antibiotic derivatives that are unlikely to induce resistance. Here, we report the very first synthetic modifications of pleuromutilin and lefamulin at alkene position C19-C20, by two different photoinduced addition reactions, the radical thiol-ene coupling reaction, and the atom transfer radical additions (ATRAs) of perfluoroalkyl iodides. Pleuromutilin were modified with the addition of several alkyl- and aryl-thiols, thiol-containing amino acids and nucleoside and carbohydrate thiols, as well as perfluoroalkylated side chains. The antibacterial properties of the novel semisynthetic pleuromutilin derivatives were investigated on a panel of bacterial strains, including susceptible and multiresistant pathogens and normal flora members. We have identified some novel semisynthetic pleuromutilin and lefamulin derivatives with promising antimicrobial properties.

The Contribution of Digital Health in the Response to Covid-19 in Vietnam.

Emerging from early of 2020, the COVID-19 pandemic has become one of the most serious health crisis globally. In response to such threat, a wide range of digital health applications has been deployed in Vietnam to strengthen surveillance, risk communication, diagnosis, and treatment of COVID-19. Digital health has brought enormous benefits to the fight against COVID-19, however, numerous constrains in digital health application remain. Lack of strong governance of digital health development and deployment; insufficient infrastructure and staff capacity for digital health application are among the main drawbacks. Despite several outstanding problems, digital health is expected to contribute to reducing the spread, improving the effectiveness of pandemic control, and adding to the dramatic transformation of the health system the post-COVID era.

Virtual mask fitting in pediatric patients during COVID-19: A case series.

INTRODUCTION: The COVID-19 pandemic has been an unprecedented threat to our health care system. Clinicians had to pivot and develop creative and timely "virtual" solutions to provide clinical care. Our aim was to develop a standardized approach to virtual "mask fitting" for children who are either being initiated or are already on existing long-term ventilation (LTV) at a pediatric hospital. CASE AND OUTCOMES: We present three cases involving the care of children who required mask fitting for noninvasive ventilation (NIV). LTV team consultations were delivered via videoconference or phone. With the guidance of the respiratory therapist (RT), the family caregiver (FC) took measurements on their child using a standardized clinical approach (developed by the LTV RTs). Based on the measurements, an appropriate mask was selected. Successful mask fit was based on patient/FC reports, as well as objective leak data obtained from the NIV download data. DISCUSSION: Virtual clinics used for managing patients in our LTV program were feasible and efficient resulting in improved workflow for the RTs and convenience for patients and FCs. Patients and FCs had significantly less pressure to attend in-person clinics and expressed high satisfaction in terms of their experience and importantly, meeting respiratory care needs. Within the context of COVID-19, remote patient education and intervention can be delivered effectively, while reducing the risk of exposure from in-person visits to hospital. CONCLUSION: A virtual/telemedicine program to manage pediatric patients requiring mask fitting for LTV was a feasible option during COVID-19.

Children and female labor market outcomes in Vietnam.

This paper examines the effect of fertility on the participation of women in the labor market and other labor market outcomes in Vietnam, using Vietnam Labor Force Survey data. To address the endogeneity issue in fertility, we use an instrumental variable estimation method based on parental preference for the mixed-sex composition of the first two children. Our findings indicate that number of children has a negative impact on maternal participation in the labor market and on working hours but has no effect on earnings. We find that the effect on participation in the market is important for younger women aged 21-35 years but insignificant for older women aged 36-50 years. The older group responds by reducing their working hours rather than leaving the labor force. Our results support the position that the rise in female participation in the labor force in Vietnam can be partially attributed to the overall decline in fertility during the last three decades and helps validate the Vietnamese government's planning policy.

Using retro-reflective cloth to enhance drivers' judgment of pedestrian walking direction at night-time.

PURPOSE: Fatal pedestrian collisions are over-represented at night and poor conspicuity is believed to be a leading causative factor. Retro-reflective clothing enhances pedestrian conspicuity, particularly when placed in a biological motion or "biomotion" configuration. In this study, we explored how various retro-reflective clothing configurations affected the ability to judge the direction of a pedestrian walking across the road, which has important implications for collision avoidance. METHODS: Participants included 21 young drivers (mean age 21.6 ±â€¯2.0 years) with normal vision. A closed-road circuit was used to assess the accuracy of drivers' judgement of the direction of walking of a pedestrian at night-time wearing one of five different clothing configurations: four with retro-reflective materials placed in different locations (Biomotion, Legs + Torso, Torso Only, Legs Only), and a control wearing only black clothing (Street). Participants were seated in a stationary vehicle with low beam headlamps, 135 m from a pedestrian, who walked across the road from both sides, in different directions (towards the car, straight across the road, or away from the car). Outcome measures included drivers' response accuracy and confidence ratings for judging pedestrian walking direction. RESULTS: Accuracy in judging pedestrian walking direction differed significantly across the clothing configurations (p < 0.001). Response accuracy was significantly higher for the Biomotion configuration (80% correct), compared to the other retro-reflective (Legs + Torso 64%; Torso Only 53%; Legs Only 50%) and Street configurations (33%). Similar trends were noted for confidence ratings across the clothing conditions, yet the relationship between confidence ratings and response accuracy within each clothing configurations was poor. CONCLUSIONS: The use of retro-reflective clothing in a biomotion configuration facilitated the highest accuracy and confidence in drivers' judgment of pedestrian walking direction, compared to other configurations. These findings highlight the importance of using biomotion clothing for pedestrians at night, to not only facilitate drivers' earlier recognition of pedestrians, but also increase their accuracy in determining the walking direction of pedestrians as they cross the road. Practical applications: The use of clothing incorporating retro-reflective material in a biomotion configuration for pedestrians crossing roads at night provides enhanced cues for drivers regarding the presence and walking direction of pedestrians.

A Cross-Sectional Study of Nemaline Myopathy.

OBJECTIVE: Nemaline myopathy (NM) is a rare neuromuscular condition with clinical and genetic heterogeneity. To establish disease natural history, we performed a cross-sectional study of NM, complemented by longitudinal assessment and exploration of pilot outcome measures. METHODS: Fifty-seven individuals with NM were recruited at 2 family workshops, including 16 examined at both time points. Participants were evaluated by clinical history and physical examination. Functional outcome measures included the Motor Function Measure (MFM), pulmonary function tests (PFTs), myometry, goniometry, and bulbar assessments. RESULTS: The most common clinical classification was typical congenital (54%), whereas 42% had more severe presentations. Fifty-eight percent of individuals needed mechanical support, with 26% requiring wheelchair, tracheostomy, and feeding tube. The MFM scale was performed in 44 of 57 participants and showed reduced scores in most with little floor/ceiling effect. Of the 27 individuals completing PFTs, abnormal values were observed in 65%. Last, bulbar function was abnormal in all patients examined, as determined with a novel outcome measure. Genotypes included mutations in ACTA1 (18), NEB (20), and TPM2 (2). Seventeen individuals were genetically unresolved. Patients with pathogenic ACTA1 and NEB variants were largely similar in clinical phenotype. Patients without genetic resolution had more severe disease. CONCLUSION: We present a comprehensive cross-sectional study of NM. Our data identify significant disabilities and support a relatively stable disease course. We identify a need for further diagnostic investigation for the genetically unresolved group. MFM, PFTs, and the slurp test were identified as promising outcome measures for future clinical trials.

Government financial support and firm productivity in vietnam.

Using the Färe-Primont index and instrumental variable fixed effect estimation for the data of small and medium-sized enterprises (SMEs), this study considers if receiving government financial support enables SMEs in Vietnam to become more productive. The paper discovers no evidence of linkage between financial support and firm productivity. However, access to financial support improves technological progress and growth in firm scale but has a negative effect on improvement in technical efficiency. The estimation results reveal that the use of productivity as an aggregated index in previous studies may hide the real effect of government support on firm productivity.

Multimodal data analysis of epileptic EEG and rs-fMRI via deep learning and edge computing.

BACKGROUND AND OBJECTIVE: Multimodal data analysis and large-scale computational capability is entering medicine in an accelerative fashion and has begun to influence investigational work in a variety of disciplines. It is also informing us of therapeutic interventions that will come about with such development. Epilepsy is a chronic brain disorder in which functional changes may precede structural ones and which may be detectable using existing modalities. METHODS: Functional connectivity analysis using electroencephalography (EEG) and resting state-functional magnetic resonance imaging (rs-fMRI) has provided such meaningful input in cases of epilepsy. By leveraging the potential of autonomic edge computing in epilepsy, we develop and deploy both noninvasive and invasive methods for monitoring, evaluation, and regulation of the epileptic brain. First, an autonomic edge computing framework is proposed for the processing of big data as part of a decision support system for surgical candidacy. Second, a multimodal data analysis using independently acquired EEG and rs-fMRI is presented for estimation and prediction of the epileptogenic network. Third, an unsupervised feature extraction model is developed for EEG analysis and seizure prediction based on a Convolutional deep learning (CNN) structure for distinguishing preictal (pre-seizure) state from non-preictal periods by support vector machine (SVM) classifier. RESULTS: Experimental and simulation results from actual patient data validate the effectiveness of the proposed methods. CONCLUSIONS: The combination of rs-fMRI and EEG/iEEG can reveal more information about dynamic functional connectivity. However, simultaneous fMRI and EEG data acquisition present challenges. We have proposed system models for leveraging and processing independently acquired fMRI and EEG data.

Overcharging of the Zinc Ion in the Structure of the Zinc-Finger Protein Is Needed for DNA Binding Stability.

Zinc-finger structure, in which a Zn2+ ion binds to four cysteines or histidines in a tetrahedral structure, is a very common motif of nucleic acid-binding proteins. The corresponding interaction model is present in 3% of the genes in the human genome. As a result, the zinc finger has been extremely useful in various therapeutic and research capacities and in biotechnology. In a stable configuration of the zinc finger, the cysteine amino acids are deprotonated and become negatively charged. Thus, the Zn2+ ion is overscreened by four cysteine charges (overcharged). Whether this overcharged configuration is also stable when such a negatively charged zinc finger binds to a negatively charged DNA molecule is unknown. We investigated how the deprotonated state of cysteine influences its structure, dynamics, and function in binding to DNA molecules by using an all-atom molecular dynamics simulation up to the microsecond range of an androgen receptor protein dimer. Our results showed that the deprotonated state of cysteine residues is essential for the mechanical stabilization of the functional, folded conformation. This state stabilizes not only the protein structure but also the protein-DNA binding complex. The differences in the structural and energetic properties of the two sequence-identical monomers are also investigated and show the strong influence of DNA on the structure of the zinc-finger protein dimer upon complexation. Our result can potentially lead to a better molecular understanding of one of the most common classes of zinc fingers.