Orphan quality control shapes network dynamics and gene expression.

All eukaryotes require intricate protein networks to translate developmental signals into accurate cell fate decisions. Mutations that disturb interactions between network components often result in disease, but how the composition and dynamics of complex networks are established remains poorly understood. Here, we identify the E3 ligase UBR5 as a signaling hub that helps degrade unpaired subunits of multiple transcriptional regulators that act within a network centered on the c-Myc oncoprotein.

Direct Outreach in Bars and Clubs to Enroll Cigarette Smokers in Mobile Cessation Services: Exploratory Study.

Background: Cigarette smoking and alcohol use are well known to be concomitant behaviors, but there is a lack of studies related to recruitment of smokers for mobile cessation services at places where alcohol is consumed, such as bars and clubs. Adapting recruitment strategies to expand the reach of cessation programs to where tobacco users are located may help decrease the health-equity gap in tobacco control by improving reach and enrollment of underserved smokers residing in low-income and rural areas who are not reached by traditional cessation services.

Objective: The purpose of this exploratory study was to assess the feasibility of direct outreach in bars, clubs, and restaurants to recruit smokers to Quitxt, our mobile smoking cessation service.

Co-adaptor driven assembly of a CUL3 E3 ligase complex.

Cullin-RING E3 ligases (CRLs) are essential ubiquitylation enzymes that combine a catalytic core built around cullin scaffolds with ∼300 exchangeable substrate adaptors. To ensure robust signal transduction, cells must constantly form new CRLs by pairing substrate-bound adaptors with their cullins, but how this occurs at the right time and place is still poorly understood. Here, we show that formation of individual CRL complexes is a tightly regulated process.

Facebook Chat Application to Prompt and Assist Smoking Cessation Among Spanish-Speaking Young Adults in South Texas.

Given how smart phones, internet services, and social media have shown great potential for assisting smoking cessation, we constructed a Facebook chat application based on our previous work with SMS texting services. This report summarizes findings from 2,364 Spanish-speaking young adults recruited through Facebook advertising in South Texas during the 2020 New Year holiday season. Among these service users, 926 (39%) were ready to make a quit attempt, and 26 (3.

Structural basis for dimerization quality control.

Most quality control pathways target misfolded proteins to prevent toxic aggregation and neurodegeneration. Dimerization quality control further improves proteostasis by eliminating complexes of aberrant composition, but how it detects incorrect subunits remains unknown. Here we provide structural insight into target selection by SCF-FBXL17, a dimerization-quality-control E3 ligase that ubiquitylates and helps to degrade inactive heterodimers of BTB proteins while sparing functional homodimers.

A Digital Health Intervention for Weight Management for Latino Families Living in Rural Communities: Perspectives and Lessons Learned During Development.

Rural residents face numerous challenges in accessing quality health care for management of chronic diseases (eg, obesity, diabetes), including scarcity of health care services and insufficient public transport. Digital health interventions, which include modalities such as internet, smartphones, and monitoring sensors, may help increase rural residents' access to health care. While digital health interventions have become an increasingly popular intervention strategy to address obesity, research examining the use of technological tools for obesity management among rural Latino populations is limited.

Technology-based health promotion: Current state and perspectives in emerging gig economy.

It has been a decade since smartphone application stores started allowing developers to post their own applications. This paper presents a narrative review on the state-of-the-art and the future of technology used by researchers in the field of mobile health promotion. Researchers build high cost, complex systems with the purpose of promoting health and collecting data.

Facilitating the development of cross-platform mHealth applications for chronic supportive care and a case study.

Mobile health (mHealth) apps have received increasing attention, due to their abilities to support patients who suffer from various conditions. mHealth apps may be especially helpful for patients with chronic diseases, by providing pertinent information, tracking symptoms, and inspiring adherence to medication regimens. To achieve these objectives, researchers need to prototype mHealth apps with dedicated software architectures.

Principles of Ubiquitin-Dependent Signaling.

Ubiquitylation is an essential posttranslational modification that controls cell division, differentiation, and survival in all eukaryotes. By combining multiple E3 ligases (writers), ubiquitin-binding effectors (readers), and de-ubiquitylases (erasers) with functionally distinct ubiquitylation tags, the ubiquitin system constitutes a powerful signaling network that is employed in similar ways from yeast to humans. Here, we discuss conserved principles of ubiquitin-dependent signaling that illustrate how this posttranslational modification shapes intracellular signaling networks to establish robust development and homeostasis throughout the eukaryotic kingdom.

Text and Mobile Media Smoking Cessation Service for Young Adults in South Texas: Operation and Cost-Effectiveness Estimation.

To realize the promising potential of services delivered via smart phones to help young adults quit smoking at a high level of cost-efficiency, we constructed a texting and mobile media system that was promoted in South Texas via social media advertising and other recruitment channels. During the 6-month service period described here, enrollments were achieved for 798 participants with a mean age of 29.3 years.

Conducting the finale of DNA replication.

Anomalies in dismantling the machinery of DNA replication can compromise genome integrity and contribute to tumorigenesis and aging. In this issue of , Dewar and colleagues (pp. 275-290) identified an E3 ubiquitin ligase, CUL2, that modifies a subunit of the replicative CMG (Cdc45, minichromosome maintenance [MCM] subunits 2-7, and the GINS complex) helicase and triggers disassembly of the replication machinery.

Chemoproteomic Screening of Covalent Ligands Reveals UBA5 As a Novel Pancreatic Cancer Target.

Chemical genetic screening of small-molecule libraries has been a promising strategy for discovering unique and novel therapeutic compounds. However, identifying the targets of lead molecules that arise from these screens has remained a major bottleneck in understanding the mechanism of action of these compounds. Here, we have coupled the screening of a cysteine-reactive fragment-based covalent ligand library with an isotopic tandem orthogonal proteolysis-enabled activity-based protein profiling (isoTOP-ABPP) chemoproteomic platform to rapidly couple the discovery of lead small molecules that impair pancreatic cancer pathogenicity with the identification of druggable hotspots for potential cancer therapy.

Regulation of the CUL3 Ubiquitin Ligase by a Calcium-Dependent Co-adaptor.

The ubiquitin ligase CUL3 is an essential regulator of neural crest specification whose aberrant activation has been linked to autism, schizophrenia, and hypertension. CUL3 exerts its roles by pairing with ∼90 distinct substrate adaptors, yet how the different CUL3-complexes are activated is poorly understood. Here, we show that CUL3 and its adaptor KLHL12 require two calcium-binding proteins, PEF1 and ALG2, for recognition of their substrate SEC31.

Phosphatidylcholine-Mediated Aqueous Diffusion of Cellular Cholesterol Down-Regulates the ABCA1 Transporter in Human Skin Fibroblasts.

Unlabelled: ATP-binding cassette protein A1 (ABCA1) is a cholesterol transporter that contributes to the active transport/removal of excess cellular cholesterol. ABCA1 expression is up-regulated when cells accumulate cholesterol.

Aims: The purpose of this study was to determine any correlation between extracellular phospholipid levels and ABCA1 expression and function.

Regulation of cargo recognition, commitment, and unloading drives cotranslational protein targeting.

Efficient and accurate protein localization is essential to cells and requires protein-targeting machineries to both effectively capture the cargo in the cytosol and productively unload the cargo at the membrane. To understand how these challenges are met, we followed the interaction of translating ribosomes during their targeting by the signal recognition particle (SRP) using a site-specific fluorescent probe in the nascent protein. We show that initial recruitment of SRP receptor (SR) selectively enhances the affinity of SRP for correct cargos, thus committing SRP-dependent substrates to the pathway.

Assessing media access and use among Latina adolescents to inform development of a physical activity promotion intervention incorporating text messaging.

Increasing physical activity (PA) during preadolescence and adolescence is critical to reversing the obesity epidemic. A recent report described the promising role of eHealth--the use of new media for purposes of health promotion--in reducing and preventing childhood obesity. This study assessed access/use of various media (cell phones, computers, gaming systems, Internet) among adolescent Latino girls and examined the relationship between PA and media access/use.

Signal recognition particle: an essential protein-targeting machine.

The signal recognition particle (SRP) and its receptor compose a universally conserved and essential cellular machinery that couples the synthesis of nascent proteins to their proper membrane localization. The past decade has witnessed an explosion in in-depth mechanistic investigations of this targeting machine at increasingly higher resolutions. In this review, we summarize recent work that elucidates how the SRP and SRP receptor interact with the cargo protein and the target membrane, respectively, and how these interactions are coupled to a novel GTPase cycle in the SRP·SRP receptor complex to provide the driving force and enhance the fidelity of this fundamental cellular pathway.

SecYEG activates GTPases to drive the completion of cotranslational protein targeting.

Signal recognition particle (SRP) and its receptor (SR) comprise a highly conserved cellular machine that cotranslationally targets proteins to a protein-conducting channel, the bacterial SecYEG or eukaryotic Sec61p complex, at the target membrane. Whether SecYEG is a passive recipient of the translating ribosome or actively regulates this targeting machinery remains unclear. Here we show that SecYEG drives conformational changes in the cargo-loaded SRP-SR targeting complex that activate it for GTP hydrolysis and for handover of the translating ribosome.

MessageSpace: a Messaging System for Health Research.

Mobile Health (mHealth) has emerged as a promising direction for delivery of healthcare services via mobile communication devices such as cell phones. Examples include texting-based interventions for chronic disease monitoring, diabetes management, control of hypertension, smoking cessation, monitoring medication adherence, appointment keeping and medical test result delivery; as well as improving patient-provider communication, health information communication, data collection and access to health records. While existing messaging systems very well support bulk messaging and some polling applications, they are not designed for data collection and processing of health research oriented studies.

Activated GTPase movement on an RNA scaffold drives co-translational protein targeting.

Approximately one-third of the proteome is initially destined for the eukaryotic endoplasmic reticulum or the bacterial plasma membrane. The proper localization of these proteins is mediated by a universally conserved protein-targeting machinery, the signal recognition particle (SRP), which recognizes ribosomes carrying signal sequences and, through interactions with the SRP receptor, delivers them to the protein-translocation machinery on the target membrane. The SRP is an ancient ribonucleoprotein particle containing an essential, elongated SRP RNA for which precise functions have remained elusive.

A tale of two GTPases in cotranslational protein targeting.

Guanosine triphosphatases (GTPases) comprise a superfamily of proteins that provide molecular switches to regulate numerous cellular processes. The "GTPase switch" paradigm, in which a GTPase acts as a bimodal switch that is turned "on" and "off" by external regulatory factors, has been used to interpret the regulatory mechanism of many GTPases. Recent work on a pair of GTPases in the signal recognition particle (SRP) pathway has revealed a distinct mode of GTPase regulation.

Lipid activation of the signal recognition particle receptor provides spatial coordination of protein targeting.

The signal recognition particle (SRP) and SRP receptor comprise the major cellular machinery that mediates the cotranslational targeting of proteins to cellular membranes. It remains unclear how the delivery of cargos to the target membrane is spatially coordinated. We show here that phospholipid binding drives important conformational rearrangements that activate the bacterial SRP receptor FtsY and the SRP-FtsY complex.