The vital role of exercise and nutrition in COVID-19 rehabilitation: synergizing strength.

Since the outset of the COVID-19 pandemic, the global healthcare community has faced the challenge of understanding and addressing the ongoing and multi-faceted SARS-CoV-2 infection outcomes. As millions of individuals worldwide continue to navigate the complexities of post-hospitalization recovery, reinfection rates, and the increasing prevalence of Long-COVID symptoms, comprehensive COVID-19 rehabilitation strategies are greatly needed. Previous studies have highlighted the potential synergy between exercise and nutrition, suggesting that their integration into patient rehabilitation programs may yield improved clinical outcomes for survivors of COVID-19. Our group aimed to consolidate existing knowledge following the implementation of patient, intervention, comparison, and outcome (PICO) search strategies on the distinct and combined impacts of exercise and nutrition interventions in facilitating the recovery of COVID-19 patients following hospitalization, with a specific focus on their implications for both public health and clinical practice. The incorporation of targeted nutritional strategies alongside exercise-based programs may expedite patient recovery, ultimately promoting independence in performing activities of daily living (ADLs). Nonetheless, an imperative for expanded scientific inquiry remains, particularly in the realm of combined interventions. This mini-review underscores the compelling prospects offered by an amalgamated approach, advocating for the seamless integration of exercise and nutrition as integral components of post-hospitalization COVID-19 rehabilitation. The pursuit of a comprehensive understanding of the synergistic effects and effectiveness of exercise and nutrition stands as a crucial objective in advancing patient care and refining recovery strategies in the wake of this enduring global health crisis.

ORFanID: A web-based search engine for the discovery and identification of orphan and taxonomically restricted genes.

With the numerous genomes sequenced today, it has been revealed that a noteworthy percentage of genes in a given taxon of organisms in the phylogenetic tree of life do not have orthologous sequences in other taxa. These sequences are commonly referred to as "orphans" or "ORFans" if found as single occurrences in a single species or as "taxonomically restricted genes" (TRGs) when found at higher taxonomic levels. Quantitative and collective studies of these genes are necessary for understanding their biological origins. However, the current software for identifying orphan genes is limited in its functionality, database search range, and very complex algorithmically. Thus, researchers studying orphan genes must harvest their data from many disparate sources. ORFanID is a graphical web-based search engine that facilitates the efficient identification of both orphan genes and TRGs at all taxonomic levels, from DNA or amino acid sequences in the NCBI database cluster and other large bioinformatics repositories. The software allows users to identify genes that are unique to any taxonomic rank, from species to domain, using NCBI systematic classifiers. It provides control over NCBI database search parameters, and the results are presented in a spreadsheet as well as a graphical display. The tables in the software are sortable, and results can be filtered using the fuzzy search functionality. The visual presentation can be expanded and collapsed by the taxonomic tree to its various branches. Example results from searches on five species and gene expression data from specific orphan genes are provided in the Supplementary Information.

Molecular Mechanisms Lead to Sex-Specific COVID-19 Prognosis and Targeted Therapies.

Clinical and epidemiological studies have identified male sex as an important risk factor for COVID-19 clinical outcomes and mortality. This raises the question as to how this risk factor can be addressed in the prognosis, clinical management, and the treatment of patients with Coronavirus disease 2019 (COVID-19). Currently, there are no guidelines or protocols to help alter the course of sex-specific COVID-19 prognosis, especially in severe disease presentations. This is partly due to the lack of research studies characterizing the differences in male vs. female host response to the severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) infection and a lack of a well-rounded understanding of the molecular mechanisms involved. Here, we discuss three distinct but interconnected molecular-level differences in males and females that likely play an essential role in the COVID-19 prognosis. We review interactions of SARS-CoV-2 with host cell angiotensin-converting enzyme 2 (ACE2) in the viral entry between males vs. females and discuss the differential regulation of the renin-angiotensin system (RAS) between the two sexes. Next, we present immune response disparities and how immune function and endocrine regulation may render males increasingly vulnerable to severe COVID-19. We describe the interconnected roles of these three regulatory systems in males and females in response to SARS-CoV-2 infection. Finally, we highlight the clinical implications of these mechanisms to patients with COVID-19 and propose putative targeted therapies that can help reduce COVID-19 severity in those critically ill.

Biopsychosocial and Spiritual Implications of Patients With COVID-19 Dying in Isolation.

Critically ill patients with the Coronavirus disease 2019 (COVID-19) are dying in isolation without the comfort of their family or other social support in unprecedented numbers. Recently, healthcare teams at COVID-19 epicenters have been inundated with critically ill patients. Patients isolated for COVID-19 have had no contact with their family or loved ones and may have likely experienced death without closure. This situation highlights concerns about patients' psychological and spiritual well-being with COVID-19 and their families, as they permanently part ways. While palliative care has advanced to adequately address these patients' needs, the COVID-19 pandemic presents several barriers that force healthcare teams to deprioritize these essential aspects of patient care. The severe acute respiratory syndrome (SARS) outbreak in 2003 gave us a glimpse of these challenges as these patients were also isolated in hospitals. Here, we discuss the importance of the biopsychosocial spiritual model in end-of-life care and its implications on patients dying with COVID-19. Furthermore, we outline an integrative approach to address the unique and holistic needs of critically ill patients dying with COVID-19. These include intentional and increased coordination with trained palliative care staff, early and frequent goals of care including discussion of end-of-life plans, broader use of technology to improve connectedness, and shared decision making with patients' families.

Systematic Review and Meta-Analysis of Sex-Specific COVID-19 Clinical Outcomes.

To successfully mitigate the extraordinary devastation caused by the Coronavirus disease 2019 (COVID-19) pandemic, it is crucial to identify important risk factors for this disease. One such neglected health determinant is the sex of the patient. This is an essential clinical characteristic, as it can factor into a patient's clinical management and preventative measures. Some clinical studies have shown disparities in the proportion between males and females that have more severe clinical outcomes or, subsequently, die from this disease. However, this association has not been unequivocally established. Thus, the purpose of this investigation was to examine the association between male sex and COVID-19 severity. We systematically reviewed the literature, identified studies that matched predetermined selection criteria, and performed a meta-analysis to evaluate the proportion of males among four disease severity categories. Appropriate assessment strategies were implemented to assess and minimize potential biases. The results of this meta-analysis indicated that males constituted a significantly higher proportion of those who had adverse clinical outcomes and died from COVID-19. As the coronavirus spread from the East to the West, male sex remained a consistent risk factor. Our results support the establishment of the male sex as an important risk factor for this disease. Early identification and appropriate medical care for males with lab-confirmed COVID-19 may substantially change the course of clinical prognosis, resulting in greater numbers of lives saved.

Molecular Nanomachines Can Destroy Tissue or Kill Multicellular Eukaryotes.

Light-activated molecular nanomachines (MNMs) can be used to drill holes into prokaryotic (bacterial) cell walls and the membrane of eukaryotic cells, including mammalian cancer cells, by their fast rotational movement, leading to cell death. We examined how these MNMs function in multicellular organisms and investigated their use for treatment and eradication of specific diseases by causing damage to certain tissues and small organisms. Three model eukaryotic species, Caenorhabditis elegans, Daphnia pulex, and Mus musculus (mouse), were evaluated. These organisms were exposed to light-activated fast-rotating MNMs and their physiological and pathological changes were studied in detail. Slow rotating MNMs were used to control for the effects of rotation rate. We demonstrate that fast-rotating MNMs caused depigmentation and 70% mortality in C. elegans while reducing the movement as well as heart rate and causing tissue damage in Daphnia. Topically applied light-activated MNMs on mouse skin caused ulceration and microlesions in the epithelial tissue, allowing MNMs to localize into deeper epidermal tissue. Overall, this study shows that the nanomechanical action of light-activated MNMs is effective against multicellular organisms, disrupting cell membranes and damaging tissue in vivo. Customized MNMs that target specific tissues for therapy combined with spatial and temporal control could have broad clinical applications in a variety of benign and malignant disease states including treatment of cancer, parasites, bacteria, and diseased tissues.

Molecular Nanomachines Disrupt Bacterial Cell Wall, Increasing Sensitivity of Extensively Drug-Resistant Klebsiella pneumoniae to Meropenem.

Multidrug resistance in pathogenic bacteria is an increasing problem in patient care and public health. Molecular nanomachines (MNMs) have the ability to open cell membranes using nanomechanical action. We hypothesized that MNMs could be used as antibacterial agents by drilling into bacterial cell walls and increasing susceptibility of drug-resistant bacteria to recently ineffective antibiotics. We exposed extensively drug-resistant Klebsiella pneumoniae to light-activated MNMs and found that MNMs increase the susceptibility to Meropenem. MNMs with Meropenem can effectively kill K. pneumoniae that are considered Meropenem-resistant. We examined the mechanisms of MNM action using permeability assays and transmission electron microscopy, finding that MNMs disrupt the cell wall of extensively drug-resistant K. pneumoniae, exposing the bacteria to Meropenem. These observations suggest that MNMs could be used to make conventional antibiotics more efficacious against multi-drug-resistant pathogens.

Near-Infrared Light Activates Molecular Nanomachines to Drill into and Kill Cells.

Using two-photon excitation (2PE), molecular nanomachines (MNMs) are able to drill through cell membranes and kill the cells. This avoids the use of the more damaging ultraviolet light that has been used formerly to induce this nanomechanical cell-killing effect. Since 2PE is inherently confocal, enormous precision can be realized. The MNMs can be targeted to specific cell surfaces through peptide addends. Further, the efficacy was verified through a controlled opening of synthetic bilayer vesicles using the 2PE excitation of MNM that had been trapped within the vesicles.

In vivo regulation of phenylalanine hydroxylase in the genetic mutant hph-1 mouse model.

The hph-1 mouse has low liver activity of GTP cyclohydrolase 1, the rate limiting enzyme in the biosynthesis of tetrahydrobiopterin (BH(4)). BH(4) is the cofactor for phenylalanine hydroxylase (PAH) and in the early stages of life the hph-1 mouse is hyperphenylalaninemic. At approximately 15 days after birth the blood phenylalanine levels normalize. During this period the animals provide an in vivo model which can be used to study the regulatory effects of phenylalanine on PAH, and for related pediatric metabolic disease in humans; from birth to youth. We therefore, examined; liver PAH activity using BH(4) and 6-methyltetrahydropterin (6MPH(4)) as cofactor; PAH total enzyme concentration by Western blotting using the PH8 antibody, and PAH state of phosphorylation using the PH7 antibody from 4 to 18 days after birth. The findings were compared to the wild type animals that are not hyperphenylalaninemic during this period. PAH (6MPH(4)) activity and total protein (PH8 antibody) rose steadily in the hph-1 mice. In control mice, both activity and total protein fluctuated. The degree of phosphorylation of PAH in the mutants and the state of activation (as measured by the 6MPH(4)/BH(4) activity ratio) increased as phenylalanine levels rose, and decreased when they fell. Similar patterns were not seen in the control animals. These studies provide in vivo evidence that phenylalanine concentration regulates the activity of PAH in the hph-1 mouse and that this acts via a mechanism that includes phosphorylation of the PAH molecule. The kinetic values (K(m) and V(max)) for mouse PAH are also reported.

Lycopene and lutein inhibit proliferation in rat prostate carcinoma cells.

Consumption of lycopene, a carotenoid without provitamin A activity, has been associated with a lower risk of prostate and breast cancer. Lutein is another carotenoid that may be associated with a reduced risk of age-related macular degeneration, the leading cause of blindness in adults 65 years of age and older. Bioactive compounds such as lycopene and lutein, derived from natural plant sources, have been shown to act at low substrate levels through the action of intrinsic cytokines and growth factors and their receptors within tissues, particularly those of the fibroblast growth factor and transforming growth factor beta families. The effects of grapefruit-derived and commercial lycopene and lutein preparations on androgen independent cultured malignant type II tumor cells [Dunning R3327AT3 or AT3 cells (androgen-responsive, slow-growing tumor cells with well developed epithelium and stroma)] were compared to their benign parent type I tumor epithelial cells (DTE). Results demonstrated that both lycopene, in an alpha -cyclodextrin water soluble carrier, and lutein inhibited malignant AT3 cells in a concentration and time-dependent manner. No such effect was observed when benign DTE cells were examined, demonstrating selective inhibition of extremely malignant AT3 prostate cancer cells relative to their benign parent. Lutein demonstrated a similar but slightly diminished response as lycopene. When cells were treated with cocktails of lycopene and lutein, no synergistic or additive effect occurred. These studies are consistent with epidemiological studies that show inverse relationships of these carotenoids with prostate cancer.