Miracle-dz/UniFAR-FTUs huggingface dataset:
National Institute for Pharmaceutical Technology & Education (NIPTE) Research and Perspective: Advances in Nanotechnology-Based Drug Delivery

For more than a decade, the National Institute for Pharmaceutical Technology & Education (NIPTE) has collaborated with industry, academia, and government on the world’s pharmaceutical challenges. NIPTE’s current membership includes seventeen US Universities with high-ranking Pharmaceutical Education and Research Programs. NIPTE has several focus groups including (1) Advanced Manufacturing, (2) Biologics & Biosimilars, (3) Translational Biomarkers, and (4) Nanotechnology. Nanotechnology has the potential to improve the formulation characteristics of drugs, improve targeting of drugs to target diseases, and reduce the adverse side effects of drugs by shifting the distribution of drugs to the target diseases. Nanotechnology also has the potential to be utilized for improved imaging of drug distribution for guiding drug delivery and disease treatment. Notably, cancer therapy and lately gene and vaccine delivery have benefited from nanotechnology. In this special theme issue, we present a collection of papers from NIPTE members focused on nanotechnology-based drug delivery and formulation research. The theme issue includes a review from Ryan Pearson and colleagues on nanoparticle-based delivery to improve the treatment of spinal cord injuries with a focus on how the implementation of multifactorial approaches to address the proinflammatory and complex immune dysfunction in spinal cord injury offers significant potential to improve outcomes (1). Chalet Tan and colleagues present research on the use of thermosensitive hydrogels for subcutaneous delivery of albumin. These hydrogels are prepared from solutions of poloxamer 407 and poly(lactide-coglycolide)-block-poly(ethylene glycol)-block-poly(lactide-coglycolide) (2). Wiwatchaitawee et al. present a review on glioblastoma multiforme (GBM) treatment strategies, summarizing current options and providing details on preclinical findings with nanoparticle-based approaches aimed at improving tumor targeting and enhancing therapeutic outcomes for GBM patients (3). Swayam Prabha and colleagues review various strategies that have been utilized for the introduction of synthetic targets in tumor tissues (4). Devika Manickam and colleagues demonstrate extracellular vesicles derived from a human brain endothelial cell line increase cellular ATP levels (5). O’Reilly Beringhs et al. present research on a nanocapsule-based platform that is promising for imageguided tumor therapy with enhanced contrastability and optimal colloidal stability (6). The research articles and reviews presented from NIPTE faculty members in this theme issue span the spectrum of drug targeting to sustained delivery and theranostics, representing important advances in nanotechnology-based drug delivery.
Rotundic acid reduces LPS‐induced acute lung injury in vitro and in vivo through regulating TLR4 dimer

Acute lung injury (ALI) is a serious clinical disease. Rotundic acid (RA), a natural ingredient isolated from Ilex rotunda Thunb, exhibits multiple pharmacological activities. However, RA's therapeutic effect and mechanism on ALI remain to be elucidated. The present study aimed to further clarify its regulating effects on inflammation in vitro and in vivo. Our results indicated that RA significantly inhibited the overproduction of interleukin‐6 (IL‐6), tumor necrosis factor‐α (TNF‐α), cyclooxygenase‐2 (COX‐2), and inducible nitric oxide synthase (iNOS). RA decreased ROS production and calcium influx. In addition, RA inhibited the activation of PI3K, MAPK, and NF‐κB pathways and enhanced the activity of nuclear factor E2‐related factor 2 (Nrf2) signaling. The cellular thermal shift assay and docking results indicated that RA bind to TLR4 to block TLR4 dimerization. Furthermore, RA pretreatment effectively inhibited ear edema induced by xylene and LPS‐induced endotoxin death and had a protective effect on LPS‐induced ALI. Our findings collectively indicated that RA has anti‐inflammatory effects, which may serve as a potential therapeutic option for pulmonary inflammation.
Does Prematurity Play a Role in Newborn Microtia-Anotia?

Objective: Microtia-anotia (MA) describes a range of external ear anomalies which is commonly associated with various syndromes and malformations of the head and neck. Previous studies have suggested a strong association between MA and male sex, maternal diabetes, and Hispanic race/ethnicity. This study seeks to evaluate the associations between MA and preterm newborns in the United States. Methods: Population-based inpatient registry analysis was conducted. Kids’ Inpatient Database (2016) was used to identify weighted in-hospital births with diagnosis of prematurity or MA. Demographic information was obtained, and odds ratios (ORs) were used to determine associations between prematurity and MA. Results: Among patients included in our dataset, 8.655% (326 285) were preterm and 0.016% (523) had MA. 0.003% (109) of patients were preterm and had MA. Preterm infants had 2.19 times the odds (95% C.I. = 1.78-2.69) of having MA when compared to the full-term population. The binary logistic regression model accounting for possible confounding variables produced an aOR of 1.48 (95% C.I. = 1.17-1.87) for the association between prematurity and MA. Conclusion: Infants who are born preterm are more likely to have MA than full term infants. The current results will allow for improved risk stratification, maternal counseling, and interventions in the case of prematurity.
Lactoferrin for Mental Health: Neuro-Redox Regulation and Neuroprotective Effects across the Blood-Brain Barrier with Special Reference to Neuro-COVID-19

Abstract Overall mental health depends in part on the blood-brain barrier, which regulates nutrient transfer in-and-out of the brain and its central nervous system. Lactoferrin, an innate metal-transport protein, synthesized in the substantia nigra, particularly in dopaminergic neurons and activated microglia is vital for brain physiology. Lactoferrin rapidly crosses the blood-brain barrier via receptor-mediated transcytosis and accumulates in the brain capillary endothelial cells. Lactoferrin receptors are additionally present on glioma cells, brain micro-vessels, and neurons. As a regulator of neuro-redox, microglial lactoferrin is critical for protection/repair of neurons and healthy brain function. Iron imbalance and oxidative stress are common among patients with neurodegenerative disorders such as Parkinson’s disease, Alzheimer’s disease, dementia, depression, and multiple sclerosis. As an endogenous iron-chelator, lactoferrin prevents iron accumulation and dopamine depletion in Parkinson’s disease patients. Oral lactoferrin supplementation could modulate the p-Akt/PTEN pathway, reduce Aβ deposition, and ameliorate cognitive decline in Alzheimer’s disease. Novel lactoferrin-based nano-therapeutics have emerged as effective drug-delivery systems for clinical management of neurodegenerative disorders. Recent emergence of the Coronavirus disease-2019 (COVID-19) pandemic, initially considered a respiratory illness, demonstrated a broader virulence spectrum with the ability to cross the blood-brain barrier and inflict a plethora of neuropathological manifestations in the brain – the Neuro-COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are widely reported in Parkinson’s disease, Alzheimer’s disease, dementia, and multiple sclerosis patients with aggravated clinical outcomes. Lactoferrin, credited with several neuroprotective benefits in the brain could serve as a potential adjuvant in the clinical management of Neuro-COVID-19.
Simlukafusp alfa (FAP-IL2v) immunocytokine is a versatile combination partner for cancer immunotherapy

ABSTRACT Simlukafusp alfa (FAP-IL2v, RO6874281/RG7461) is an immunocytokine comprising an antibody against fibroblast activation protein α (FAP) and an IL-2 variant with a retained affinity for IL-2Rβγ > IL-2 Rβγ and abolished binding to IL-2 Rα. Here, we investigated the immunostimulatory properties of FAP-IL2v and its combination with programmed cell death protein 1 (PD-1) checkpoint inhibition, CD40 agonism, T cell bispecific and antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies. The binding and immunostimulatory properties of FAP-IL2v were investigated in vitro and compared with FAP-IL2wt. Tumor targeting was investigated in tumor-bearing mice and in a rhesus monkey. The ability of FAP-IL2v to potentiate the efficacy of different immunotherapies was investigated in different xenograft and syngeneic murine tumor models. FAP-IL2v bound IL-2 Rβγ and FAP with high affinity in vitro, inducing dose-dependent proliferation of natural killer (NK) cells and CD4+/CD8+ T cells while being significantly less potent than FAP-IL2wt in activating immunosuppressive regulatory T cells (Tregs). T cells activated by FAP-IL2v were less sensitive to Fas-mediated apoptosis than those activated by FAP-IL2wt. Imaging studies demonstrated improved tumor targeting of FAP-IL2v compared to FAP-IL2wt. Furthermore, FAP-IL2v significantly enhanced the in vitro and in vivo activity of therapeutic antibodies that mediate antibody-dependent or T cell-dependent cellular cytotoxicity (TDCC) and of programmed death-ligand 1 (PD-L1) checkpoint inhibition. The triple combination of FAP-IL2v with an anti-PD-L1 antibody and an agonistic CD40 antibody was most efficacious. These data indicate that FAP-IL2v is a potent immunocytokine that potentiates the efficacy of different T- and NK-cell-based cancer immunotherapies.
Proteomic and Transcriptomic Analysis of Microviridae φX174 Infection Reveals Broad Upregulation of Host Escherichia coli Membrane Damage and Heat Shock Responses

A major part of the healthy human gut microbiome is the Microviridae bacteriophage, exemplified by the model φX174 phage, and their E. coli hosts. Although much has been learned from studying φX174 over the last half-century, until this work, the E. coli host response to infection has never been investigated in detail. ABSTRACT Measuring host-bacteriophage dynamics is an important approach to understanding bacterial survival functions and responses to infection. The model Microviridae bacteriophage φX174 is endemic to the human gut and has been studied for over 70 years, but the host response to infection has never been investigated in detail. To address this gap in our understanding of this important interaction within our microbiome, we have measured host Escherichia coli C proteomic and transcriptomic response to φX174 infection. We used mass spectrometry and RNA sequencing (RNA-seq) to identify and quantify all 11 φX174 proteins and over 1,700 E. coli proteins, enabling us to comprehensively map host pathways involved in φX174 infection. Most notably, we see significant host responses centered on membrane damage and remodeling, cellular chaperone and translocon activity, and lipoprotein processing, which we speculate is due to the peptidoglycan-disruptive effects of the φX174 lysis protein E on MraY activity. We also observe the massive upregulation of small heat shock proteins IbpA/B, along with other heat shock pathway chaperones, and speculate on how the specific characteristics of holdase protein activity may be beneficial for viral infections. Together, this study enables us to begin to understand the proteomic and transcriptomic host responses of E. coli to Microviridae infections and contributes insights to the activities of this important model host-phage interaction. IMPORTANCE A major part of the healthy human gut microbiome is the Microviridae bacteriophage, exemplified by the model φX174 phage, and their E. coli hosts. Although much has been learned from studying φX174 over the last half-century, until this work, the E. coli host response to infection has never been investigated in detail. We reveal the proteomic and transcriptomic pathways differentially regulated during the φX174 infection cycle and uncover the details of a coordinated cellular response to membrane damage that results in increased lipoprotein processing and membrane trafficking, likely due to the phage antibiotic-like lysis protein. We also reveal that small heat shock proteins IbpA/B are massively upregulated during infection and that these holdase chaperones are highly conserved across the domains of life, indicating that reliance on them is likely widespread across viruses.
Between the city and the farm: food environments in artisanal mining communities in Upper Guinea

Abstract Objective: Artisanal and small-scale mining (ASM) is a widespread livelihood in low- and middle-income countries; however, many in ASM communities face high levels of poverty and malnutrition. The food environments in ASM communities have non-agricultural rural characteristics that differ from those in urban and agricultural rural areas examined in much existing food environment literature. Design: We examine these complex external and personal food environments in ASM communities via a study using qualitative and quantitative methods. Market surveys and a cross-sectional household survey, plus qualitative mining site non-participant observations and in-depth structured interviews, were conducted in three waves. Setting: Eighteen study sites in ASM communities in northern Guinea. Participants: Surveys covered mothers in mining households with young children (n 613); in-depth interviews engaged caregivers of young children (n 45), food vendors (n 40) and young single miners (n 15); observations focused on mothers of young children (n 25). Results: The external food environment in these ASM communities combines widespread availability of commercially processed and staple-heavy foods with lower availability and higher prices for more nutritious, non-staple foods. Within the personal food environment, miners are constrained in their food choices by considerable variability in daily cash income and limited time for acquisition and preparation. Conclusions: We demonstrate that ASM communities have characteristics of both urban and rural populations and argue for greater nuance and appreciation of complexity in food environment research and resultant policy and programming.
Riboflavin fortification of rice endosperm by metabolic engineering

Riboflavin (vitamin B2 ) is an essential nutrient for human health and body development. Riboflavin deficiency may increase the risk of some diseases (Thakur et al., 2017). Humans must regularly consume a sufficient amount of riboflavin, as this vitamin cannot be stored in the body. Data from the 2010-2012 China National Nutrition and Health Surveillance indicated that the riboflavin dietary intake of 85.9% of 14- to 17-year-old Chinese participants was below the estimated average requirement (Wang et al., 2017).
Cotranscriptional splicing efficiencies differ within genes and between cell types

Pre-mRNA splicing is carried out by the spliceosome and involves splice site recognition, removal of introns, and ligation of exons. Components of the spliceosome have been shown to interact with the elongating RNA polymerase II (RNAPII), which is thought to allow splicing to occur concurrently with transcription. However, little is known about the regulation and efficiency of cotranscriptional splicing in human cells. In this study, we used Bru-seq and BruChase-seq to determine the cotranscriptional splicing efficiencies of 17,000 introns expressed across six human cell lines. We found that less than half of all introns across these six cell lines were cotranscriptionally spliced. Splicing efficiencies for individual introns showed variations across cell lines, suggesting that splicing may be regulated in a cell type–specific manner. Moreover, the splicing efficiency of introns varied within genes. The efficiency of cotranscriptional splicing did not correlate with gene length, intron position, splice site strengths, or the intron/neighboring exons GC content. However, we identified binding signals from multiple RNA-binding proteins (RBPs) that correlated with splicing efficiency, including core spliceosomal machinery components—such as SF3B4, U2AF1, and U2AF2 showing higher binding signals in poorly spliced introns. In addition, multiple RBPs, such as BUD13, PUM1, and SND1, showed preferential binding in exons that flank introns with high splicing efficiencies. The nascent RNA splicing patterns presented here across multiple cell types add to our understanding of the complexity in RNA splicing, wherein RNA-binding proteins may play important roles in determining splicing outcomes in a cell type– and intron-specific manner.
The Daily Experience of Subjective Tinnitus: Ecological Momentary Assessment Versus End-of-Day Diary

Objective: Traditional methods of self-report assessments are susceptible to bias (i.e., memory, recall, and recency). Ecological momentary assessment (EMA) may curb these biases by repeated momentary assessment of the participant throughout the day. High costs and participant burden may, however, impede the use of EMA. End-of-day diary (EDD) provides an attractive alternative to EMA, though no direct comparison has been performed in the tinnitus field. Design: Four thousand seven-hundred thirty-two data entries were collected from nine participants undergoing cognitive behavioral treatment for tinnitus. Eleven equivalent EMA and EDD items were collected for approximately 3 months. Tinnitus experience (i.e., anger, annoyance, avoidance, distraction, fear, invasiveness, pleasantness, and sadness) and well-being (i.e., anxiety, happiness, and stress) were correlated and means compared (t-tests). Results: All variables presented adequate correlation (r > 0.68) between the EMA and EDD counterparts. Small (<3.9%) significant daily mean differences between EMA and EDD were found for six variables (tinnitus anger, invasiveness, pleasantness, sadness, as well as anxiety and stress) with worse results reported in EDD. Conclusion: The small significant effects found may be attributed to the large number of data points. When EMA is not possible or recommended, EDD provides a viable alternative to assess tinnitus experience daily. Further research on the underlying mechanisms of tinnitus experience and recollection is warranted.
Implantation of the Vibrant Soundbridge in a Case of Bilateral Malformation of the Middle and External Ear

Patient: Female, 13-year-old Final Diagnosis: Bilateral congenital external and middle ear malformation Symptoms: Hearing loss Medication: — Clinical Procedure: — Specialty: Otolaryngology Objective: Congenital defects/diseases Background: Here we present a case of Vibrant Soundbridge implantation in a 13-year-old girl with bilateral aural atresia of the external ear canal. In this instance, we attached the device’s floating mass transducer (FMT) to a mobilizable complex of the incus and malleus, which functionally connected to the short process of the incus. Case Report: The article presents a case study of a patient with a congenital defect of the middle and external ear and conductive hearing loss, who was referred for middle ear implantation. Tonal audiometry revealed bilateral moderate to severe hearing loss with a 30 to 50 dB air-bone gap. After making a sufficiently wide antromastoidectomy, it became apparent that implantation of the MedEl Bonebridge hearing aid was not possible because of an overhanging dura. The short process of the incus was then visualized and, by drilling the bone laterally and anteriorly, the incus and malleus were found to have formed a conglomerate, firmly fused to the anterior wall of a rather small tympanic cavity. By removing the bony adhesion, mobility of the ossicular chain was restored. The MedEl Vibrant Soundbridge could then be implanted by attaching its FMT to the incus-like conglomerate. Conclusions: Restoration of ossicular chain mobility was achieved, and the patient’s hearing was improved by implanting the Vibrant Soundbridge hearing aid. Speech audiometry 1 month later showed improved hearing. Implantation of the Vibrant Soundbridge following ossiculoplasty may be a feasible solution in cases of bilateral congenital defect of the middle and external ear.
Excellent Outcome in Living Donor Liver Transplantation: Treating Patients With Acute‐on‐Chronic Liver Failure

Acute‐on‐chronic liver failure (ACLF) is a fatal condition, and liver transplantation (LT) is a vital option for these patients. However, the result of living donor LT (LDLT) for ACLF is not well investigated. This study investigated the outcomes of LDLT in patients with ACLF compared with patients without ACLF. This was a single‐center, retrospective, matched case‐control study. From July 2002 to March 2017, a total of 112 patients with ACLF who underwent LDLT were enrolled according to the consensus of the Asian Pacific Association for the Study of the Liver. A total of 224 patients were selected for control comparison (non‐ACLF) with demographic factors (sex, age, and body mass index) matched (1:2). Patients with ACLF were stratified into ACLF 1, 2, and 3 categories according to the number of organ failures based on the Chronic Liver Failure–Sequential Organ Failure Assessment score. Survival and surgical outcomes after LDLT were analyzed. The Model for End‐Stage Liver Disease and Child‐Turcotte‐Pugh scores in the ACLF group were significantly higher than those in the non‐ACLF group (P < 0.001). The 90‐day, 3‐year, and 5‐year survival rates in the ACLF and non‐ACLF groups were 97.3%, 95.5%, 92.9%, respectively, and 96.9%, 94.2%, and 91.1%, respectively (P = 0.58). There was more intraoperative blood loss in the ACLF group than in the non‐ACLF group (P < 0.001). The other postoperative complications were not significantly different between the groups. A total of 20 patients (17.9%) in the ACLF group presented with 3 or more organ system dysfunctions (ACLF 3), and the 90‐day, 3‐year, and 5‐year survival rates were comparable with those of ACLF 1 and ACLF 2 (P = 0.25). In carefully selected patients, LDLT gives excellent outcomes in patients with ACLF regardless of the number of organs involved. Comprehensive perioperative care and timely transplantation play crucial roles in saving the lives of patients with ACLF.