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BackgroundSupporting patients to self-manage their chronic kidney disease (CKD) has been identified as a research priority by patients with CKD and those who care for them. Self-management has been shown to slow CKD progression and improve the quality of life of individuals living with the disease. Previous work has identified a need for a person-centered, theory-informed, web-based tool for CKD self-management that can be individualized to a patient’s unique situation, priorities, and preferences. We addressed this gap using an integrated knowledge translation method and patient engagement principles. ObjectiveThe aim of this study is to conduct systematic co-design and usability testing of a web-based self-management prototype for adults with CKD (nondialysis and nontransplant) and their caregivers to enhance self-management support. MethodsA multistep, iterative system development cycle was used to co-design and test the My Kidneys My Health prototype. The 3-step process included creating website features and content using 2 sequential focus groups with patients with CKD and caregivers, heuristic testing using the 10 heuristic principles by Nielsen, and usability testing through in-person 60-minute interviews with patients with CKD and their caregivers. Patients with CKD, caregivers, clinicians, researchers, software developers, graphic designers, and policy makers were involved in all steps of this study. ResultsIn step 1, 18 participants (14 patients and 4 caregivers) attended one of the 2 sequential focus groups. The participants provided specific suggestions for simplifying navigation as well as suggestions to incorporate video, text, audio, interactive components, and visuals to convey information. A total of 5 reviewers completed the heuristic analysis (step 2), identifying items mainly related to navigation and functionality. Furthermore, 5 participants completed usability testing (step 3) and provided feedback on video production, navigation, features and functionality, and branding. Participants reported visiting the website repeatedly for the following features: personalized food tool, my health care provider question list, symptom guidance based on CKD severity, and medication advice. Usability was high, with a mean system usability score of 90 out of 100. ConclusionsThe My Kidneys My Health prototype is a systematically developed, multifaceted, web-based CKD self-management support tool guided by the theory and preferences of patients with CKD and their caregivers. The website is user friendly and provides features that improve user experience by tailoring the content and resources to their needs. A feasibility study will provide insights into the acceptability of and engagement with the prototype and identify preliminary patient-reported outcomes (eg, self-efficacy) as well as potential factors related to implementation. This work is relevant given the shift to virtual care during the current pandemic times and provides patients with support when in-person care is restricted.

Nematode molting is a remarkable process where animals must repeatedly build a new apical extracellular matrix (aECM) beneath a previously built aECM that is subsequently shed. The nuclear hormone receptor NHR-23 (also known as NR1F1) is an important regulator of C. elegans molting. NHR-23 expression oscillates in the epidermal epithelium, and soma-specific NHR-23 depletion causes severe developmental delay and death. Tissue-specific RNAi suggests that nhr-23 acts primarily in seam and hypodermal cells. NHR-23 coordinates the expression of factors involved in molting, lipid transport/metabolism and remodeling of the aECM. NHR-23 depletion causes dampened expression of a nas-37 promoter reporter and a loss of reporter oscillation. The cuticle collagen ROL-6 and zona pellucida protein NOAH-1 display aberrant annular localization and severe disorganization over the seam cells after NHR-23 depletion, while the expression of the adult-specific cuticle collagen BLI-1 is diminished and frequently found in patches. Consistent with these localization defects, the cuticle barrier is severely compromised when NHR-23 is depleted. Together, this work provides insight into how NHR-23 acts in the seam and hypodermal cells to coordinate aECM regeneration during development.

Lysosomes are an important organelle required for the degradation of a range of cellular components. Lysosome function is critical for development and homeostasis as dysfunction can lead to inherited genetic disorders, cancer, and neurodegenerative and metabolic diseases. The acidic and protease-rich environment of lysosomes poses experimental challenges. Many fluorescent proteins are quenched or degraded, while specific red fluorescent proteins can be cleaved from translational fusion partners and accumulate. While studying MLT-11, a Caenorhabditis elegans molting factor that localizes to lysosomes and the cuticle, we sought to optimize several experimental parameters. We found that, in contrast to mNeonGreen fusions, mScarlet fusions to MLT-11 missed cuticular and rectal epithelial localization. Rapid sample lysis and denaturation were critical for preventing MLT-11 fragmentation while preparing lysates for western blots. Using a model lysosomal substrate (NUC-1), we found that rigid polyproline linkers and truncated mCherry constructs do not prevent cleavage of mCherry from NUC-1. We provide evidence that extended localization in lysosomal environments prevents the detection of FLAG epitopes in western blots. Finally, we optimize an acid-tolerant green fluorescent protein (Gamillus) for use in C. elegans. These experiments provide important experimental considerations and new reagents for the study of C. elegans lysosomal proteins.

WHEN MY wife and I moved away from the Midwest some fifteen years ago, we began an age of perpetual homesickness. I'd tear up at the sight of Notre Dame's [...]

A reported increase of hookworm and strongyloidiasis transmission in rural Alabama, USA, in 2017 (1) has led to more interest in isolated cases of autochthonous transmission of soil-transmitted helminths in [...]

We engineered a fluorescent fusion protein of C. elegans lamin, by fusing the eleventh beta strand of GFP to the N-terminus of LMN-1 at the endogenous lmn-1 locus. When co-expressed with GFP1-10, GFP11::LMN-1 was observed at the nuclear periphery of a wide variety of somatic cells. Homozygous gfp11::lmn-1 animals had normal numbers of viable embryos. However, the gfp11::lmn-1 animals had a mild swimming defect. While not completely functional, the GFP11::LMN-1 strain is more healthy than other published fluorescent LMN-1 lines, making it a valuable reagent for studying lamins.

Spermatogenesis is the process through which mature male gametes are formed and is necessary for the transmission of genetic information. While much work has established how sperm fate is promoted and maintained, less is known about how the sperm morphogenesis program is executed. We previously identified a novel role for the nuclear hormone receptor transcription factor, NHR-23, in promoting Caenorhabditis elegans spermatogenesis. The depletion of NHR-23 along with SPE-44, another transcription factor that promotes spermatogenesis, caused additive phenotypes. Through RNA-seq, we determined that NHR-23 and SPE-44 regulate distinct sets of genes. The depletion of both NHR-23 and SPE-44 produced yet another set of differentially regulated genes. NHR-23-regulated genes are enriched in phosphatases, consistent with the switch from genome quiescence to post-translational regulation in spermatids. In the parasitic nematode Ascaris suum, MFP1 and MFP2 control the polymerization of Major Sperm Protein, the molecule that drives sperm motility and serves as a signal to promote ovulation. NHR-23 and SPE-44 regulate several MFP2 paralogs, and NHR-23 depletion from the male germline caused defective localization of MSD/MFP1 and NSPH-2/MFP2. Although NHR-23 and SPE-44 do not transcriptionally regulate the casein kinase gene spe-6, a key regulator of sperm development, SPE-6 protein is lost following NHR-23+SPE-44 depletion. Together, these experiments provide the first mechanistic insight into how NHR-23 promotes spermatogenesis and an entry point to understanding the synthetic genetic interaction between nhr-23 and spe-44.

We describe a previously unappreciated role for Bruton's tyrosine kinase (BTK) in fungal immune surveillance against aspergillosis, an unforeseen complication of BTK inhibitors (BTKi) used for treating B cell lymphoid malignancies. We studied BTK-dependent fungal responses in neutrophils from diverse populations, including healthy donors, patients who were treated with BTKi, and X-linked agammaglobulinemia patients. Upon fungal exposure, BTK was activated in human neutrophils in a TLR2-, Dectin-1-, and Fc[gamma]R-dependent manner, triggering the oxidative burst. BTK inhibition selectively impeded neutrophil-mediated damage to Aspergillus hyphae, primary granule release, and the fungus-induced oxidative burst by abrogating NADPH oxidase subunit [p40.sup.phox] and GTPase RAC2 activation. Moreover, neutrophil-specific Btk deletion in mice enhanced aspergillosis susceptibility by impairing neutrophil function, not recruitment or lifespan. Conversely, GM-CSF partially mitigated these deficits by enhancing [p47.sup.phox] activation. Our findings underline the crucial role of BTK signaling in neutrophils for antifungal immunity and provide a rationale for GM-CSF use to offset these deficits in patients who are susceptible., Introduction Invasive aspergillosis (IA), most often caused by the ubiquitous inhaled mold Aspergillus fumigatus, is an opportunistic fungal infection that exploits numeric or functional neutrophil defects (1-3). IA affects over [...]

The deleterious nature of U.S. economic recessions over the last several decades highlight a need to investigate the role of family economic strain on families. The current study explored the impact of family economic strain on marital quality and marital stability through dyadic associations of marital support and work-family conflict of 370 married couples over a 12-year period (1989-2001) through an actor-partner interdependence model, encompassing two major U.S. recessions. Guided by family stress and coping theory, findings are consistent with past research indicating the negative impact of family economic strain on marital quality and marital stability; however, this impact may be mitigated through the mediation of positive perceptions of marital support and work-family conflict. Implications suggest financial counselors should consider the lasting influence of economic strain on families, and how the psychosocial resources of martial support and managing work-family conflict may promote relationship quality and stability.

Auxin-inducible degradation is a powerful tool for the targeted degradation of proteins with spatiotemporal control. One limitation of the auxin-inducible degradation system is that not all proteins are degraded efficiently. Here, we demonstrate that an alternative degron sequence, termed mIAA7, improves the efficiency of degradation in Caenorhabditiselegans, as previously reported in human cells. We tested the depletion of a series of proteins with various subcellular localizations in different tissue types and found that the use of the mIAA7 degron resulted in faster depletion kinetics for 5 out of 6 proteins tested. The exception was the nuclear protein HIS-72, which was depleted with similar efficiency as with the conventional AID* degron sequence. The mIAA7 degron also increased the leaky degradation for 2 of the tested proteins. To overcome this problem, we combined the mIAA7 degron with the C. elegans AID2 system, which resulted in complete protein depletion without detectable leaky degradation. Finally, we show that the degradation of ERM-1, a highly stable protein that is challenging to deplete, could be improved further by using multiple mIAA7 degrons. Taken together, the mIAA7 degron further increases the power and applicability of the auxin-inducible degradation system. To facilitate the generation of mIAA7-tagged proteins using CRISPR/Cas9 genome engineering, we generated a toolkit of plasmids for the generation of dsDNA repair templates by PCR.

We describe a case of a 2-year-old child who expelled a single adult female Ascaris lumbricoides worm. The patient is from a rural county in Mississippi, USA, with no reported travel outside of the United States. The caregivers in the home practice good sanitation. Exposure to domestic pigs is the likely source of infection.

Founded in 1800, Edinoverie was considered, at least by some of its twentieth-century proponents, to be a vessel for preserving Old Believer culture within the Russian Orthodox Church. Typically, historians have approached Edinoverie either in terms of policy development and theological disputation in the empire’s capitals or through the example of single regions. The article outlines the main trends in the development of Edinoverie in the nineteenth — early twentieth centuries on a nationwide scale. The work also presents a comparative study of Edinoverie parishes in the Perm and Nizhny Novgorod Governorates. The process of emergence and spread of Edinoverie in these regions is analyzed. The changes that the Edinoverie went through in different periods of its existence are noted. At the micro level, the life of Edinoverie parishes, the characteristics of the Edinoverie clergy, the problems of parishioners, the relationship of Edinoverie with the Orthodox episcopate are analyzed. As the article shows, in both parishes there were indeed similar problems in the development of the deanery, such as difficult relations with both the “official” Orthodox and Old Believers groups. However, significant differences can be noted. The dissatisfaction of Edinovertsy with the rules of Metropolitan Platon, which regulated the existence of Edinoverie in the Russian Orthodox Church, is noted. The Urals tried to solve this problem at the turn of the 1830s–1840s, de facto implementing the project of “Edinoverie on special conditions,” which was aimed at increasing the autonomy of Edinoverstsy by reassigning them to secular authorities. The Nizhny Novgorod attempt to resolve this issue occurred in 1877 and was aimed at changing the very rules of Metropolitan Platon.