An effective immune response requires the engagement of host receptors by pathogen‐derived molecules and the stimulation of an appropriate cellular response. Therefore, a crucial factor in our ...ability to control an infection is the accessibility of our immune cells to the foreign material. Exosomes—which are extracellular vesicles that function in intercellular communication—may play a key role in the dissemination of pathogen‐ as well as host‐derived molecules during infection. In this review, we highlight the composition and function of exosomes and other extracellular vesicles produced during viral, parasitic, fungal and bacterial infections and describe how these vesicles could function to either promote or inhibit host immunity.
Exosomes and other extracellular vesicles mediate intercellular communication. Pathogen‐induced vesicles are key to pathogen dissemination and modulate immune responses in their favor, but also to help the host combat infectious disease.
The human brain weighs approximately 2% of the body; however, it consumes about 20% of a person’s total energy intake. Cellular bioenergetics in the central nervous system involves a delicate balance ...between biochemical processes engaged in energy conversion and those responsible for respiration. Neurons have high energy demands, which rely on metabolic coupling with glia, such as with oligodendrocytes and astrocytes. It has been well established that astrocytes recycle and transport glutamine to neurons to make the essential neurotransmitters, glutamate and GABA, as well as shuttle lactate to support energy synthesis in neurons. However, the metabolic role of oligodendrocytes in the central nervous system is less clear. In this review, we discuss the energetic demands of oligodendrocytes in their survival and maturation, the impact of altered oligodendrocyte energetics on disease pathology, and the role of energetic metabolites, taurine, creatine, N-acetylaspartate, and biotin, in regulating oligodendrocyte function.
Remdesivir (RDV; GS-5734) is currently the only FDA-approved antiviral drug for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The drug is approved for use ...in adults or children 12 years or older who are hospitalized for the treatment of COVID-19 on the basis of an acceleration of clinical recovery for inpatients with this disease. Unfortunately, the drug must be administered intravenously, restricting its use to those requiring hospitalization for relatively advanced disease. RDV is also unstable in plasma and has a complex activation pathway which may contribute to its highly variable antiviral efficacy in SARS-CoV-2-infected cells. Potent orally bioavailable antiviral drugs for early treatment of SARS-CoV-2 infection are urgently needed, and several, including molnupiravir and PF-07321332, are currently in clinical development. We focused on making simple, orally bioavailable lipid analogs of remdesivir nucleoside (RVn; GS-441524) that are processed to RVn monophosphate, the precursor of the active RVn triphosphate, by a single-step intracellular cleavage. In addition to high oral bioavailability, stability in plasma, and simpler metabolic activation, new oral lipid prodrugs of RVn had submicromolar anti-SARS-CoV-2 activity in a variety of cell types, including Vero E6, Calu-3, Caco-2, human pluripotent stem cell (PSC)-derived lung cells, and Huh7.5 cells. In Syrian hamsters, oral treatment with 1-
-octadecyl-2-
-benzyl-glycero-3-phosphate RVn (ODBG-P-RVn) was well tolerated and achieved therapeutic levels in plasma above the 90% effective concentration (EC
) for SARS-CoV-2. The results suggest further evaluation as an early oral treatment for SARS-CoV-2 infection to minimize severe disease and reduce hospitalizations.
Exosomes are extracellular vesicles of endocytic origin that function in intercellular communication. Our previous studies indicate that exosomes released from Mycobacterium tuberculosis-infected ...macrophages contain soluble mycobacterial proteins. However, it was unclear how these secreted proteins were targeted to exosomes. In this study, we determined that exosome production by the murine macrophage cell line RAW264.7 requires the endosomal sorting complexes required for transport and that trafficking of mycobacterial proteins from phagocytosed bacilli to exosomes was dependent on protein ubiquitination. Moreover, soluble mycobacterial proteins, when added exogenously to RAW264.7 or human HEK293 cells, were endocytosed, ubiquitinated, and released via exosomes. This suggested that endocytosed proteins could be recycled from cells through exosomes. This hypothesis was supported using the tumor-associated protein He4, which, when endocytosed by RAW264.7 or HEK293 cells, was transported to exosomes in a ubiquitin-dependent manner. Our data suggest that ubiquitination is a modification sufficient for trafficking soluble proteins within the phagocytic/endocytic network to exosomes.
Mycobacterium tuberculosis-infected macrophages and dendritic cells are limited in their ability to present antigen to CD4+ T cells suggesting that other mechanism of antigen presentation are driving ...the robust T cell response observed during an M. tuberculosis infection. These mechanisms could include antigens present in apoptotic bodies, necrotic debris, exosomes or even release of non-vesicular antigen from infected cells. However, there is limited data to support any of these mechanisms as important in driving T cell activation in vivo. In the present study we use Rab27a-deficient mice which show diminished trafficking of mycobacterial components to exosomes as well as M. tuberculosis strains that express recombinant proteins which traffic or fail to traffic to exosomes. We observed that exosomes released during a mouse M. tuberculosis infection contribute significantly to its T cell response. These finding imply that exosomes function to promote T cell immunity during a bacterial infection and are an important source of extracellular antigen.
A wide range of diseases have been shown to be influenced by the accumulation of senescent cells, from fibrosis to diabetes, cancer, Alzheimer's and other age-related pathologies. Consistent with ...this, clearance of senescent cells can prolong healthspan and lifespan in in vivo models. This provided a rationale for developing a new class of drugs, called senolytics, designed to selectively eliminate senescent cells in human tissues. The senolytics tested so far lack specificity and have significant off-target effects, suggesting that a targeted approach could be more clinically relevant. Here, we propose to use an extracellular epitope of B2M, a recently identified membrane marker of senescence, as a target for the specific delivery of toxic drugs into senescent cells. We show that an antibody-drug conjugate (ADC) against B2M clears senescent cells by releasing duocarmycin into them, while an isotype control ADC was not toxic for these cells. This effect was dependent on p53 expression and therefore more evident in stress-induced senescence. Non-senescent cells were not affected by either antibody, confirming the specificity of the treatment. Our results provide a proof-of-principle assessment of a novel approach for the specific elimination of senescent cells using a second generation targeted senolytic against proteins of their surfaceome, which could have clinical applications in pathological ageing and associated diseases.
Summary
Background
Chronic constipation affects approximately 17% of the population worldwide and remains an important unmet need since patients are often dissatisfied with treatment. Kiwifruit may ...offer an alternative to traditional laxatives and have been shown to increase stool volume, frequency and improve consistency.
Aims
Using non‐invasive MRI techniques, we assessed the effect of ingestion of kiwifruit on fluid distribution in the intestines and bowel function.
Methods
Two period crossover trial of kiwifruit vs control in healthy adults. Intervention: two kiwifruits twice daily vs isocaloric control (maltodextrin) twice daily, consumed for a total of 3 days. Subjects underwent MRI scanning fasted and at hourly intervals for 7 hours on the third day. Primary outcome: T1 relaxation time of ascending colon (T1AC) using MRI. Secondary outcomes: Small bowel water content (SBWC), colonic volume, gut transit time, T1 of descending colon, stool frequency and form.
Results
Fourteen volunteers completed the study. T1AC was higher after kiwifruit ingestion (P = 0.029) during the second half of the day (when meal residue would be expected to reach the AC, AUC T1 T240‐420 minutes; mean (SD) 137 (39) s*minute with kiwifruit versus 108 (40) s*minute with control. SBWC (P < 0.001), colon volumes (P = 0.004), as well as stool frequency (1.46 ± 0.66 with kiwifruit vs 1.14 ± 0.46 stools per day with control; P = 0.034) and stool form score (Bristol Stool Chart score 4.1 (0.9) with kiwifruit versus 3.4 (0.7) with control; P = 0.011) were markedly increased in participants consuming kiwifruit compared to control.
Conclusion
Consumption of kiwifruit in healthy volunteers increases water retention in the small bowel and ascending colon and increases total colonic volume. The data may explain the observed increase in stool frequency and looser stool consistencies, suggesting that kiwifruit could be used as a dietary alternative to laxatives in mild constipation.
At a recent consensus conference, the Malignant Hyperthermia Association of the United States addressed 6 important and unresolved clinical questions concerning the optimal management of patients ...with malignant hyperthermia (MH) susceptibility or acute MH. They include(1) How much dantrolene should be available in facilities where volatile agents are not available or administered, and succinylcholine is only stocked on site for emergency purposes? (2) What defines masseter muscle rigidity? What is its relationship to MH, and how should it be managed when it occurs? (3) What is the relationship between MH susceptibility and heat- or exercise-related rhabdomyolysis? (4) What evidence-based interventions should be recommended to alleviate hyperthermia associated with MH? (5) After treatment of acute MH, how much dantrolene should be administered and for how long? What criteria should be used to determine stopping treatment with dantrolene? (6) Can patients with a suspected personal or family history of MH be safely anesthetized before diagnostic testing? This report describes the consensus process and the outcomes for each of the foregoing unanswered clinical questions.
There is increasing scientific and clinical attention to chronic irritability in youth. However, little is known about the predictive validity and clinical significance of chronic irritability during ...early childhood. This prospective, longitudinal study examined associations of chronic irritability with psychiatric disorders and parental psychopathology in a large community sample of preschoolers.
Four hundred sixty-two preschool-age children were assessed at 3 and 6 years of age. Child psychopathology was assessed at baseline (3 years) and follow-up (6 years) using a diagnostic interview, the Preschool Age Psychiatric Assessment, with parents. Items from the Preschool Age Psychiatric Assessment were used to create a dimensional measurement of chronic irritability. Parental psychopathology was assessed with a diagnostic interview at baseline.
Chronic irritability was concurrently associated with a wide range of psychiatric disorders and functional impairment at 3 and 6 years of age. Irritability at 3 years predicted depression, oppositional defiant disorder, and functional impairment at 6 years after controlling for baseline disorders. Irritability also was associated with parental depression and anxiety.
Findings underscore the central role of irritability in early-emerging mental health problems. They are consistent with longitudinal studies in older youth indicating that chronic irritability predicts later depression and anxiety and support the importance of early detection and interventions targeting preschool irritability.
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