Second-Generation Cap Analogue Prodrugs for Targeting Aberrant Eukaryotic Translation Initiation Factor 4E Activity in Cancer.

Dysregulation of translation is a hallmark of cancer that enables rapid changes in cellular protein production to shape oncogenic phenotypes. Translation initiation is governed by the mGpppX cap-binding protein eukaryotic translation initiation factor 4E (eIF4E), the rate-limiting factor of cap-dependent translation initiation. eIF4E is overexpressed in many cancers and drives the production of oncoproteins that promote tumor growth and survival.

Novel mTORC2/HSPB4 Interaction: Role and Regulation of HSPB4 T148 Phosphorylation.

HSPB4 and HSPB5 (α-crystallins) have shown increasing promise as neuroprotective agents, demonstrating several anti-apoptotic and protective roles in disorders such as multiple sclerosis and diabetic retinopathy. HSPs are highly regulated by post-translational modification, including deamidation, glycosylation, and phosphorylation. Among them, T148 phosphorylation has been shown to regulate the structural and functional characteristics of HSPB4 and underlie, in part, its neuroprotective capacity.

SARS-CoV-2 and HSV-1 Induce Amyloid Aggregation in Human CSF Resulting in Drastic Soluble Protein Depletion.

The corona virus (SARS-CoV-2) pandemic and the resulting long-term neurological complications in patients, known as long COVID, have renewed interest in the correlation between viral infections and neurodegenerative brain disorders. While many viruses can reach the central nervous system (CNS) causing acute or chronic infections (such as herpes simplex virus 1, HSV-1), the lack of a clear mechanistic link between viruses and protein aggregation into amyloids, a characteristic of several neurodegenerative diseases, has rendered such a connection elusive. Recently, we showed that viruses can induce aggregation of purified amyloidogenic proteins via the direct physicochemical mechanism of heterogeneous nucleation (HEN).

Systemic increase in IL-26 is associated with severe COVID-19 and comorbid obstructive lung disease.

Background: IL-26 is a key mediator of pulmonary host defense given its abundant expression in human airways and its established antibacterial properties. Moreover, recent studies indicate that IL-26 can also inhibit viral replication. Along these lines, we have previously reported an increase in the plasma concentration of IL-26 among patients with acute COVID-19 that is linked to harmful hyperinflammation.

Second-Generation Cap Analogue Prodrugs for Targeting Aberrant Eukaryotic Translation Initiation Factor 4E (eIF4E) Activity in Drug-Resistant Melanoma.

Melanoma is the deadliest form of skin cancer with a 5-year survival rate of less than 20%. While significant strides have been made in the field of kinase-targeted and immune-based therapies for melanoma, the development of resistance to these therapeutic agents has hindered the success of treatment. Drug-resistant melanoma is particularly reliant on enhanced cap-dependent translation to drive the production of oncoproteins that promote growth and survival.

Longitudinal associations between prenatal internalizing symptoms and mindfulness traits with postnatal bonding difficulties.

Purpose: Mothers' reported connection, or bond, with their infants develops across the early postnatal period and is relevant to mother and offspring functioning. Little is known, however, about early predictors of bonding difficulties over time. The present study examined prenatal anxiety, depressive symptoms, and trait mindfulness and variation in bonding difficulties in mothers across the first two months postnatal.

A comparison of smartphone and infrasound microphone data from a fuel air explosive and a high explosive.

For prompt detection of large (>1 kt) above-ground explosions, infrasound microphone networks and arrays are deployed at surveyed locations across the world. Denser regional and local networks are deployed for smaller explosions, however, they are limited in number and are often deployed temporarily for experiments. With the expanded interest in smaller yield explosions targeted at vulnerable areas such as population centers and key infrastructures, the need for more dense microphone networks has increased.

Germline prediction of immune checkpoint inhibitor discontinuation for immune-related adverse events.

Introduction: Immune checkpoint inhibitors (ICIs) can yield remarkable clinical responses in subsets of patients with solid tumors but can also often lead to immune-related adverse events (irAEs). Predictive features of clinically severe irAEs leading to cessation of ICIs have yet to be established. Using data from 1,327 patients with lung cancer treated with ICIs between 2009 and 2022 at four academic medical centers, we evaluated the association of a germline polygenic risk score for autoimmune disease and discontinuation of ICIs due to irAEs.

Polygenic risk score for ulcerative colitis predicts immune checkpoint inhibitor-mediated colitis.

Immune checkpoint inhibitor-mediated colitis (IMC) is a common adverse event of treatment with immune checkpoint inhibitors (ICI). We hypothesize that genetic susceptibility to Crohn's disease (CD) and ulcerative colitis (UC) predisposes to IMC. In this study, we first develop a polygenic risk scores for CD (PRS) and UC (PRS) in cancer-free individuals and then test these PRSs on IMC in a cohort of 1316 patients with ICI-treated non-small cell lung cancer and perform a replication in 873 ICI-treated pan-cancer patients.

Patients' and caregivers' experiences of virtual care in a primary care setting during the COVID-19 pandemic: A patient-oriented research study.

Objective: This study explored patient and caregiver expectations and experiences of virtual primary care in Manitoba, Canada. This study focused on accessibility of care, acceptability and perceptions of quality from 'users' of primary healthcare services. Due to the rapid implementation of virtual primary care during the COVID-19 pandemic in Canada, patient/public input was largely bypassed.

Immunogenicity, Efficacy, and Safety of a Novel Synthetic Microparticle Pre-Erythrocytic Malaria Vaccine in Multiple Host Species.

We previously reported a protective antibody response in mice immunized with synthetic microparticle vaccines made using layer-by-layer fabrication (LbL-MP) and containing the conserved T1BT* epitopes from the circumsporozoite protein. To further optimize the vaccine candidate, a benchtop tangential flow filtration method (LbL-by-TFF) was developed and utilized to produce vaccine candidates that differed in the status of base layer crosslinking, inclusion of a TLR2 ligand in the antigenic peptide, and substitution of serine or alanine for an unpaired cysteine residue in the T* epitope. Studies in mice revealed consistent superiority of the Pam3Cys-modified candidates and a modest benefit of base layer crosslinking, as evidenced by higher and more persistent antibody titers (up to 18 months post-immunization), a qualitative improvement of T-cell responses toward a Th1 phenotype, and greater protection from live parasite challenges compared to the unmodified prototype candidate.

Infant Nutrition and Other Early Life Risk Factors for Childhood Obesity According to Disability Status.

One in five preschool-aged children in the United States is obese, and children with disabilities are significantly impacted. This study aimed to determine the association between age at solid food initiation and obesity prevalence in preschool-aged children while considering disability status, ethnicity, gestational age, and birth weight. Analysis was conducted on a sample of 145 children aged 2 to 5 years who were enrolled in ten childcare centers.

Neural reactivity to infant emotion cues during pregnancy: Associations with peripartum anxiety and depressive symptoms.

Background: Pregnancy is marked by physiological and psychosocial changes for women, and event-related potentials (ERP) are comfortable and safe for examining brain function across pregnancy. The late positive potential (LPP) ERP, a measure of allocated attention to emotional stimuli, may provide insight into associations between internalizing symptoms and neural processing of infant emotion cues, which may be particularly salient in this life stage.

Methods: We developed a task to examine neural and behavioral responses to infant faces in pregnant women (N = 120, Mage=31.

Targeting positive valence systems function in children of mothers with depressive symptoms: A pilot randomized trial of an RDoC-Informed preventive intervention.

Reduced activation of the Research Domain Criteria (RDoC) positive valence systems (PVS) is observed in high-risk (HR) children of depressed mothers and predictive of future psychopathologies. We developed a dyadic, neuroscience-informed preventive intervention, Family Promoting Positive Emotions (FPPE), designed to prevent psychopathology in HR children by targeting PVS processes. We evaluated the initial efficacy of FPPE compared to written information (WI) psychoeducation in engaging PVS-related targets and reducing perceived stress and emotional distress symptoms in HR youth.

Design of Cell-Permeable Inhibitors of Eukaryotic Translation Initiation Factor 4E (eIF4E) for Inhibiting Aberrant Cap-Dependent Translation in Cancer.

Eukaryotic translation initiation factor 4E (eIF4E) is an RNA-binding protein that binds to the mGpppX-cap at the 5' terminus of coding mRNAs to initiate cap-dependent translation. While all cells require cap-dependent translation, cancer cells become addicted to enhanced translational capacity, driving the production of oncogenic proteins involved in proliferation, evasion of apoptosis, metastasis, and angiogenesis, among other cancerous phenotypes. eIF4E is the rate-limiting translation factor, and its activation has been shown to drive cancer initiation, progression, metastasis, and drug resistance.

Design of Cell-Permeable Inhibitors of Eukaryotic Translation Initiation Factor 4E (eIF4E) for Inhibiting Aberrant Cap-Dependent Translation in Cancer.

Eukaryotic translation initiation factor 4E (eIF4E) is an RNA-binding protein that binds to the m GpppX-cap at the 5' terminus of coding mRNAs to initiate cap-dependent translation. While all cells require cap-dependent translation, cancer cells become addicted to enhanced translational capacity, driving the production of oncogenic proteins involved in proliferation, evasion of apoptosis, metastasis, and angiogenesis among other cancerous phenotypes. eIF4E is the rate-limiting translation factor and its activation has been shown to drive cancer initiation, progression, metastasis, and drug resistance.

TLR4-mediated release of heparin-binding protein in human airways: a co-stimulatory role for IL-26.

Background: Bacterial infection causes accumulation of neutrophils that release antimicrobial proteins including heparin-binding protein (HBP). In human airways, this neutrophil accumulation can be re-capitulated via intrabronchial exposure to lipopolysaccharide (LPS), a Toll-like receptor 4 (TLR4) agonist, that also causes a local increase in the neutrophil-mobilizing cytokine IL-26. Although LPS is considered a weak stimulus for HBP release , its effect on HBP release in human airways has not been characterized.

Social Challenges as a Consequence of the COVID-19 Pandemic among South Florida Preschool Children with Disability and Obesity.

The COVID-19 pandemic has negatively impacted the childcare industry over the past two years. This study examined how pandemic-related challenges impacted preschool-aged children by disability and obesity status. Participants were 216 children (80% Hispanic, 14% non-Hispanic Black) aged 2 to 5 years in 10 South Florida childcare centers.

Benevolent Childhood Experiences and Childhood Maltreatment History: Examining their Roles in Depressive Symptoms Across the Peripartum Period.

Peripartum depressive symptoms are associated with a range of adverse outcomes for offspring and mothers. Childhood experiences, both negative and positive, may impact peripartum depression risk. Longitudinal studies are needed to examine trajectories of change in depression across the peripartum and predictors of symptoms across time.

Neural Predictors of Improvement With Cognitive Behavioral Therapy for Adolescents With Depression: An Examination of Reward Responsiveness and Emotion Regulation.

Earlier depression onsets are associated with more debilitating courses and poorer life quality, highlighting the importance of effective early intervention. Many youths fail to improve with evidence-based treatments for depression, likely due in part to heterogeneity within the disorder. Multi-method assessment of individual differences in positive and negative emotion processing could improve predictions of treatment outcomes.