HEPN RNases - an emerging class of functionally distinct RNA processing and degradation enzymes.

HEPN (Higher Eukaryotes and Prokaryotes Nucleotide-binding) RNases are an emerging class of functionally diverse RNA processing and degradation enzymes. Members are defined by a small α-helical bundle encompassing a short consensus RNase motif. HEPN dimerization is a universal requirement for RNase activation as the conserved RNase motifs are precisely positioned at the dimer interface to form a composite catalytic center. While the core HEPN fold is conserved, the organization surrounding the HEPN dimer can support large structural deviations that contribute to their specialized functions. HEPN RNases are conserved throughout evolution and include bacterial HEPN RNases such as CRISPR-Cas and toxin-antitoxin associated nucleases, as well as eukaryotic HEPN RNases that adopt large multi-component machines. Here we summarize the canonical elements of the growing HEPN RNase family and identify molecular features that influence RNase function and regulation. We explore similarities and differences between members of the HEPN RNase family and describe the current mechanisms for HEPN RNase activation and inhibition.

Capillary Assembly of Anisotropic Particles at Cylindrical Fluid-Fluid Interfaces.

The unique behavior of colloids at liquid interfaces provides exciting opportunities for engineering the assembly of colloidal particles into functional materials. The deformable nature of fluid-fluid interfaces means that we can use the interfacial curvature, in addition to particle properties, to direct self-assembly. To this end, we use a finite element method (Surface Evolver) to study the self-assembly of rod-shaped particles adsorbed at a simple curved fluid-fluid interface formed by a sessile liquid drop with cylindrical geometry. Specifically, we study the self-assembly of single and multiple rods as a function of drop curvature and particle properties such as shape (ellipsoid, cylinder, and spherocylinder), contact angle, aspect ratio, and chemical heterogeneity (homogeneous and triblock patchy). We find that the curved interface allows us to effectively control the orientation of the rods, allowing us to achieve parallel, perpendicular, or novel obliquely orientations with respect to the cylindrical drop. In addition, by tuning particle properties to achieve parallel alignment of the rods, we show that the cylindrical drop geometry favors tip-to-tip assembly of the rods, not just for cylinders, but also for ellipsoids and triblock patchy rods. Finally, for triblock patchy rods with larger contact line undulations, we can achieve strong spatial confinement of the rods transverse to the cylindrical drop due to the capillary repulsion between the contact line undulations of the particle and the pinned contact lines of the sessile drop. Our capillary assembly method allows us to manipulate the configuration of single and multiple rod-like particles and therefore offers a facile strategy for organizing such particles into useful functional materials.

Efficient Copper-Catalyzed Highly Stereoselective Synthesis of Unprotected C-Acyl Manno-, Rhamno- and Lyxopyranosides.

Due to their high stability towards enzymatic hydrolysis C-acyl glycosidic compounds are useful synthetic intermediates for potential candidates in drug discovery. Syntheses for C-acyl mannosides have remained scarce and usually employ donors obtained from lengthy syntheses. Furthermore, syntheses of unprotected C-acyl mannosides have not been reported so far, due to the incapability of the C-acyl mannoside motif with deprotection conditions for protective groups commonly used in carbohydrate chemistry. Herein, we report an efficient and highly α-selective four-step one-pot method for the synthesis of C-acyl α-d-manno-, l-rhamno- and d-lyxopyranosides from easily accessible persilylated monosaccharides and dithianes requiring only trace amounts of a copper source as catalyst and explain the crucial role of the catalyst by mechanistic studies. Furthermore, the C-acyl α-glycosides were easily isomerized to give rapid access to their ß-anomers.

It takes two (Las1 HEPN endoribonuclease domains) to cut RNA correctly.

The ribosome biogenesis factor Las1 is an essential endoribonuclease that is well-conserved across eukaryotes and a newly established member of the higher eukaryotes and prokaryotes nucleotide-binding (HEPN) domain-containing nuclease family. HEPN nucleases participate in diverse RNA cleavage pathways and share a short HEPN nuclease motif (RφXXXH) important for RNA cleavage. Most HEPN nucleases participate in stress-activated RNA cleavage pathways; Las1 plays a fundamental role in processing pre-rRNA. Underscoring the significance of Las1 function in the cell, mutations in the human LAS1L (LAS1-like) gene have been associated with neurological dysfunction. Two juxtaposed HEPN nuclease motifs create Las1's composite nuclease active site, but the roles of the individual HEPN motif residues are poorly defined. Here using a combination of in vivo experiments in Saccharomyces cerevisiae and in vitro assays, we show that both HEPN nuclease motifs are required for Las1 nuclease activity and fidelity. Through in-depth sequence analysis and systematic mutagenesis, we determined the consensus HEPN motif in the Las1 subfamily and uncovered its canonical and specialized elements. Using reconstituted Las1 HEPN-HEPN' chimeras, we defined the molecular requirements for RNA cleavage. Intriguingly, both copies of the Las1 HEPN motif were important for nuclease function, revealing that both HEPN motifs participate in coordinating the RNA within the Las1 active site. We also established that conformational flexibility of the two HEPN domains is important for proper nuclease function. The results of our work reveal critical information about how dual HEPN domains come together to drive Las1-mediated RNA cleavage.

A comparison of dominance rank metrics reveals multiple competitive landscapes in an animal society.

Across group-living animals, linear dominance hierarchies lead to disparities in access to resources, health outcomes and reproductive performance. Studies of how dominance rank predicts these traits typically employ one of several dominance rank metrics without examining the assumptions each metric makes about its underlying competitive processes. Here, we compare the ability of two dominance rank metrics-simple ordinal rank and proportional or 'standardized' rank-to predict 20 traits in a wild baboon population in Amboseli, Kenya. We propose that simple ordinal rank best predicts traits when competition is density-dependent, whereas proportional rank best predicts traits when competition is density-independent. We found that for 75% of traits (15/20), one rank metric performed better than the other. Strikingly, all male traits were best predicted by simple ordinal rank, whereas female traits were evenly split between proportional and simple ordinal rank. Hence, male and female traits are shaped by different competitive processes: males are largely driven by density-dependent resource access (e.g. access to oestrous females), whereas females are shaped by both density-independent (e.g. distributed food resources) and density-dependent resource access. This method of comparing how different rank metrics predict traits can be used to distinguish between different competitive processes operating in animal societies.

Mechanobiology of mice cervix: expression profile of mechano-related molecules during pregnancy.

There is a known reciprocation between the chronic exertion of force on tissue and both increased tissue density (e.g., bone) and hypertrophy (e.g., heart). This can also be seen in cervical tissue where the excessive gravitational forces associated with multiple fetal pregnancies promote preterm births. While there is a well-known regulation of cervical remodeling (CR) by sex steroid hormones and growth factors, the role of mechanical force is less appreciated. Using proteome-wide technology, we previously provided evidence for the presence of and alteration in mechano-related signaling molecules in the mouse cervix during pregnancy. Here, we profile the expression of select cytoskeletal factors (filamin-A, gelsolin, vimentin, actinin-1, caveolin-1, transgelin, keratin-8, profilin-1) and their associated signaling molecules [focal adhesion kinase (FAK) and the Rho GTPases CDC42, RHOA, and RHOB] in cervices of pregnant mice by real-time PCR and confocal immunofluorescence microscopy. Messenger RNA and protein levels increased for each of these 12 factors, except for 3 (keratin-8, profilin-1, RHOA) that decreased during the course of pregnancy and this corresponded with an increase in gravitational force exerted by the fetus on the cervix. We therefore conclude that size or weight of the growing fetus likely plays a key role in CR through mechanotransduction processes.

Vernakalant for cardioversion of recent-onset atrial fibrillation: a systematic review and meta-analysis.

AIMS: To evaluate the efficacy and safety of vernakalant for the cardioversion of atrial fibrillation (AF). METHODS AND RESULTS: We reviewed the literature for randomized trials that compared vernakalant to another drug or placebo in patients with AF of onset ≤7 days. We used a random-effects model to combine quantitative data and rated the quality of evidence using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation). From 441 total citations in MEDLINE, EMBASE, and CENTRAL (December 2018), we identified nine trials evaluating 1358 participants. Six trials compared vernakalant to placebo, two trials compared vernakalant to ibutilide, and one trial compared vernakalant to amiodarone. We found significant methodological bias in four trials. For conversion within 90 min, vernakalant was superior to placebo [50% conversion, risk ratio (RR) 5.15; 95% confidence interval (CI); 2.24-11.84, I2 = 91%], whereas we found no significant difference in conversion when vernakalant was compared with an active drug (56% vs. 24% conversion, RR 2.40; 95% CI 0.76-7.58, I2 = 94). Sinus rhythm was maintained at 24 h in 85% (95% CI 80-88%) of patients who converted acutely with vernakalant. Overall, we judged the quality of evidence for efficacy to be low based on inconsistency and suspected publication bias. There was no significant difference in the risk of significant adverse events between vernakalant and comparator (RR 0.95; 95% CI 0.70-1.28, I2 = 0, moderate quality evidence). Vernakalant is safe and effective for rapid and durable restoration of sinus rhythm in patients with recent-onset AF. CONCLUSION: Vernakalant should be a first line option for the pharmacological cardioversion of patients with haemodynamically stable recent-onset AF without severe structural heart disease.

Conditional fetal and infant killing by male baboons.

Sexually selected feticide-the death of infants in utero as a result of male behaviour-has only rarely been described or analysed, although it is presumed to be favoured by the same selective pressures that favour sexually selected infanticide. To test this hypothesis, we measured the frequency of feticide and infanticide by male baboons of the Amboseli basin in Kenya, and examined which characteristics of a male and his environment made him more likely to commit feticide and/or infanticide. We found a dramatic increase in fetal and infant death rates, but no increase in death rates of 1- to 2-year-old individuals, following the immigration of males who stood to benefit from feticide and infanticide. Specifically, fetal and infant death rates were highest following immigrations in which: (i) the immigrant male rapidly attained high rank, (ii) that male remained consistently resident in the group for at least three months, (iii) food availability and social group range overlap was relatively low and (iv) relatively many pregnant females and/or dependent infants were present. Together, these results provide strong evidence for the existence of both sexually selected feticide and infanticide in our population, and they indicate that feticide and infanticide are conditional male behavioural strategies employed under particular circumstances.

Experiences of Successful PrEP Uptake Among Adolescent Sexual Minority Men in the United States: A Qualitative Exploration.

Male adolescent sexual minorities are at elevated risk of HIV acquisition yet demonstrate low rates of PrEP uptake. Understanding the experiences of adolescents who have successfully accessed PrEP may inform ways to best support adolescents seeking PrEP. Adolescent sexual minorities (N = 100) who reported utilizing PrEP responded to open-ended items asking about their initial PrEP experiences and advice for others. Qualitative analysis suggested that adolescents' ability to access PrEP is influenced by managing parental involvement and seeking culturally competent health care providers. Additionally, they reported how the benefits and drawbacks of taking PrEP played a role in their PrEP use. Findings suggest that educational PrEP interventions targeted at this population could improve uptake by incorporating discussions on side effects and mental health benefits associated with PrEP use. Structural interventions are warranted that improve adolescents' ability to seek sexual health care independently and make room for parental involvement when adolescents could benefit from their support.

Preclinical Characterization of AZD9574, a Blood-Brain Barrier Penetrant Inhibitor of PARP1.

PURPOSE: We evaluated the properties and activity of AZD9574, a blood-brain barrier (BBB) penetrant selective inhibitor of PARP1, and assessed its efficacy and safety alone and in combination with temozolomide (TMZ) in preclinical models. EXPERIMENTAL DESIGN: AZD9574 was interrogated in vitro for selectivity, PARylation inhibition, PARP-DNA trapping, the ability to cross the BBB, and the potential to inhibit cancer cell proliferation. In vivo efficacy was determined using subcutaneous as well as intracranial mouse xenograft models. Mouse, rat, and monkey were used to assess AZD9574 BBB penetration and rat models were used to evaluate potential hematotoxicity for AZD9574 monotherapy and the TMZ combination. RESULTS: AZD9574 demonstrated PARP1-selectivity in fluorescence anisotropy, PARylation, and PARP-DNA trapping assays and in vivo experiments demonstrated BBB penetration. AZD9574 showed potent single agent efficacy in preclinical models with homologous recombination repair deficiency in vitro and in vivo. In an O6-methylguanine-DNA methyltransferase (MGMT)-methylated orthotopic glioma model, AZD9574 in combination with TMZ was superior in extending the survival of tumor-bearing mice compared with TMZ alone. CONCLUSIONS: The combination of three key features-PARP1 selectivity, PARP1 trapping profile, and high central nervous system penetration in a single molecule-supports the development of AZD9574 as the best-in-class PARP inhibitor for the treatment of primary and secondary brain tumors. As documented by in vitro and in vivo studies, AZD9574 shows robust anticancer efficacy as a single agent as well as in combination with TMZ. AZD9574 is currently in a phase I trial (NCT05417594). See related commentary by Lynce and Lin, p. 1217.

Large-scale Pan-cancer Cell Line Screening Identifies Actionable and Effective Drug Combinations.

Oncology drug combinations can improve therapeutic responses and increase treatment options for patients. The number of possible combinations is vast and responses can be context-specific. Systematic screens can identify clinically relevant, actionable combinations in defined patient subtypes. We present data for 109 anticancer drug combinations from AstraZeneca's oncology small molecule portfolio screened in 755 pan-cancer cell lines. Combinations were screened in a 7 × 7 concentration matrix, with more than 4 million measurements of sensitivity, producing an exceptionally data-rich resource. We implement a new approach using combination Emax (viability effect) and highest single agent (HSA) to assess combination benefit. We designed a clinical translatability workflow to identify combinations with clearly defined patient populations, rationale for tolerability based on tumor type and combination-specific "emergent" biomarkers, and exposures relevant to clinical doses. We describe three actionable combinations in defined cancer types, confirmed in vitro and in vivo, with a focus on hematologic cancers and apoptotic targets. SIGNIFICANCE: We present the largest cancer drug combination screen published to date with 7 × 7 concentration response matrices for 109 combinations in more than 750 cell lines, complemented by multi-omics predictors of response and identification of "emergent" combination biomarkers. We prioritize hits to optimize clinical translatability, and experimentally validate novel combination hypotheses. This article is featured in Selected Articles from This Issue, p. 695.

New Zealanders with low back pain seeking health care: a retrospective descriptive analysis of Accident Compensation Corporation-funded low back pain healthcare service usage.

Introduction Most New Zealanders experience low back pain (LBP) at least once throughout their lifetime and many seek help from the large range of health providers in primary care. Accident Compensation Corporation (ACC) funds a significant proportion of those claims, but which services are they funding and what are the costs? Method This was a retrospective audit and descriptive analysis of ACC-funded, non-public hospital healthcare service use by people with LBP in New Zealand (NZ). Outcome measures were the healthcare services accessed by people with ACC-funded LBP,the claims (all occurrences for a service that has generated a payment/year), single contact (with a service), and costs (NZ$) for services between 2009 and 2020. Results The number of claims for services were 129 000 for physiotherapy, 105 000 for general practitioner and 59 000 for radiology services. Per single contact, elective surgery and radiology services were the most expensive. During 2009-2020, there were 3.3 million ACC claims for LBP with a total cost of NZ$4 billion. Over this time, there was an increase in claims, costs and single contacts. Costs decreased slightly during 2010 due to changes in healthcare funding and in 2020 due to the COVID-19 pandemic. Discussion Consumers have considerable choice in where they access health care for ACC-funded LBP services. This study shows the services they use most frequently and the cost to NZ for those services. These data can inform service planning for ACC-funded LBP health care in NZ.

Social Support-Seeking Strategies on Social Media at the Intersection of Lesbian, Gay, Bisexual, Transgender, and Queer Identity, Race, and Ethnicity: Insights for Intervention From a Qualitative Study.

BACKGROUND: Lesbian, gay, bisexual, transgender, and queer (LGBTQ+) individuals experience a disproportionately higher prevalence of mental health challenges when compared to their heterosexual and cisgender counterparts. Moreover, they exhibit increased engagement with social media platforms relative to their peers. Understanding the intersectional dynamics of their identities is crucial in elucidating effective and safe approaches to garnering social support through social media channels. This exploration holds significance for informing future research endeavors and shaping targeted interventions to address the unique mental health needs of LGBTQ+ individuals. OBJECTIVE: The purpose of this study was to explore the strategies used by Black, Hispanic, and non-Hispanic White LGBTQ+ young adults to acquire social support from social media. The study aimed to examine how these strategies may differ by race and ethnicity. METHODS: We conducted semistructured interviews with LGBTQ+ young adults aged between 18 and 30 years recruited in the United States from social media. Of 52 participants, 12 (23%) were Black, 12 (23%) were Hispanic, and 28 (54%) were non-Hispanic White. Thematic analysis was used to analyze the collected data. RESULTS: The analysis uncovered both divergent and convergent strategies among participants of different races and ethnicities. Black and Hispanic young adults exhibited a preference for connecting with individuals who shared similar identities, seeking safety and tailored advice. Conversely, non-Hispanic White participants demonstrated minimal preference for identity-based advice. Seeking support from anonymous sources emerged as a strategy to avoid unwanted disclosure among Hispanic participants. Furthermore, all participants emphasized the importance of content filtering with family members to cultivate positive and supportive social media experiences. CONCLUSIONS: This study sheds light on the strategies used by LGBTQ+ individuals of different racial and ethnic backgrounds to seek social support from social media platforms. The findings underscore the importance of considering race and ethnicity when examining social support-seeking behaviors on social media in LGBTQ+ populations. The identified strategies provide valuable insights for the development of interventions that aim to leverage social support from social media to benefit the mental health of Black, Hispanic, and non-Hispanic White LGBTQ+ young adults.

Nucleolar Architecture Is Modulated by a Small Molecule, the Inositol Pyrophosphate 5-InsP7.

Inositol pyrophosphates (PP-InsPs); are a functionally diverse family of eukaryotic molecules that deploy a highly-specialized array of phosphate groups as a combinatorial cell-signaling code. One reductive strategy to derive a molecular-level understanding of the many actions of PP-InsPs is to individually characterize the proteins that bind them. Here, we describe an alternate approach that seeks a single, collective rationalization for PP-InsP binding to an entire group of proteins, i.e., the multiple nucleolar proteins previously reported to bind 5-InsP7 (5-diphospho-inositol-1,2,3,4,6-pentakisphosphate). Quantitative confocal imaging of the outer nucleolar granular region revealed its expansion when cellular 5-InsP7 levels were elevated by either (a) reducing the 5-InsP7 metabolism by a CRISPR-based knockout (KO) of either NUDT3 or PPIP5Ks; or (b), the heterologous expression of wild-type inositol hexakisphosphate kinase, i.e., IP6K2; separate expression of a kinase-dead IP6K2 mutant did not affect granular volume. Conversely, the nucleolar granular region in PPIP5K KO cells shrank back to the wild-type volume upon attenuating 5-InsP7 synthesis using either a pan-IP6K inhibitor or the siRNA-induced knockdown of IP6K1+IP6K2. Significantly, the inner fibrillar volume of the nucleolus was unaffected by 5-InsP7. We posit that 5-InsP7 acts as an 'electrostatic glue' that binds together positively charged surfaces on separate proteins, overcoming mutual protein-protein electrostatic repulsion the latter phenomenon is a known requirement for the assembly of a non-membranous biomolecular condensate.

Effects of internalised racism and internalised homophobia on sexual behaviours among black gay and bisexual men in the USA: a systematic review protocol.

INTRODUCTION: Black gay and bisexual men are overburdened by HIV in the USA. While the socioecological model has been applied to understand potential mechanisms of HIV acquisition among black gay and bisexual men, there is mixed evidence on the impact of internalised stigma on HIV risk among this population. This systematic review protocol paper outlines the systematic review being conducted to determine the relationship between internalised racism, internalised homophobia and engagement in sexual behaviour, which puts individuals at risk for HIV infection. METHODS AND ANALYSIS: For the review, we will conduct a systematic review of the literature, summarise and critique published scholarly literature on the associations between forms of internalised stigma and sexual behaviours among black gay and bisexual men. We will conduct a systematic search of published qualitative and quantitative research studies published during and after 1993. The searches will be conducted in Ovid Medline, Ovid APA PsycInfo and EBSCO SocINDEX databases. Studies will be included if they were conducted in the USA, with samples that comprised African American/black cisgender gay, bisexual, queer and other men who have sex with men, measured internalised racism and/or internalised homophobia, and assessed sexual behaviour risk for HIV acquisition. ETHICS AND DISSEMINATION: No ethical approval will be required for this review. We will report our findings using the guidelines outlined by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Findings of this review may offer new opportunities to study internalised mechanisms impacting outcomes and to identify research gaps and spur additional queries in the group most disproportionately impacted by HIV.

Cryo-EM reveals the architecture of the PELP1-WDR18 molecular scaffold.

PELP1 (Proline-, Glutamic acid-, Leucine-rich protein 1) is a large scaffolding protein that functions in many cellular pathways including steroid receptor (SR) coactivation, heterochromatin maintenance, and ribosome biogenesis. PELP1 is a proto-oncogene whose expression is upregulated in many human cancers, but how the PELP1 scaffold coordinates its diverse cellular functions is poorly understood. Here we show that PELP1 serves as the central scaffold for the human Rix1 complex whose members include WDR18, TEX10, and SENP3. We reconstitute the mammalian Rix1 complex and identified a stable sub-complex comprised of the conserved PELP1 Rix1 domain and WDR18. We determine a 2.7 Å cryo-EM structure of the subcomplex revealing an interconnected tetrameric assembly and the architecture of PELP1's signaling motifs, including eleven LxxLL motifs previously implicated in SR signaling and coactivation of Estrogen Receptor alpha (ERα) mediated transcription. However, the structure shows that none of these motifs is in a conformation that would support SR binding. Together this work establishes that PELP1 scaffolds the Rix1 complex, and association with WDR18 may direct PELP1's activity away from SR coactivation.

Synchrony and idiosyncrasy in the gut microbiome of wild baboons.

Human gut microbial dynamics are highly individualized, making it challenging to link microbiota to health and to design universal microbiome therapies. This individuality is typically attributed to variation in host genetics, diets, environments and medications but it could also emerge from fundamental ecological forces that shape microbiota more generally. Here, we leverage extensive gut microbial time series from wild baboons-hosts who experience little interindividual dietary and environmental heterogeneity-to test whether gut microbial dynamics are synchronized across hosts or largely idiosyncratic. Despite their shared lifestyles, baboon microbiota were only weakly synchronized. The strongest synchrony occurred among baboons living in the same social group, probably because group members range over the same habitat and simultaneously encounter the same sources of food and water. However, this synchrony was modest compared to each host's personalized dynamics. In support, host-specific factors, especially host identity, explained, on average, more than three times the deviance in longitudinal dynamics compared to factors shared with social group members and ten times the deviance of factors shared across the host population. These results contribute to mounting evidence that highly idiosyncratic gut microbiomes are not an artefact of modern human environments and that synchronizing forces in the gut microbiome (for example, shared environments, diets and microbial dispersal) are not strong enough to overwhelm key drivers of microbiome personalization, such as host genetics, priority effects, horizontal gene transfer and functional redundancy.

Excessive energy expenditure due to acute physical restraint disrupts Drosophila motivational feeding response.

To study the behavior of Drosophila, it is often necessary to restrain and mount individual flies. This requires removal from food, additional handling, anesthesia, and physical restraint. We find a strong positive correlation between the length of time flies are mounted and their subsequent reflexive feeding response, where one hour of mounting is the approximate motivational equivalent to ten hours of fasting. In an attempt to explain this correlation, we rule out anesthesia side-effects, handling, additional fasting, and desiccation. We use respirometric and metabolic techniques coupled with behavioral video scoring to assess energy expenditure in mounted and free flies. We isolate a specific behavior capable of exerting large amounts of energy in mounted flies and identify it as an attempt to escape from restraint. We present a model where physical restraint leads to elevated activity and subsequent faster nutrient storage depletion among mounted flies. This ultimately further accelerates starvation and thus increases reflexive feeding response. In addition, we show that the consequences of the physical restraint profoundly alter aerobic activity, energy depletion, taste, and feeding behavior, and suggest that careful consideration is given to the time-sensitive nature of these highly significant effects when conducting behavioral, physiological or imaging experiments that require immobilization.

Inhibition of Scavenger Receptor Class B Type 1 (SR-B1) Expression and Activity as a Potential Novel Target to Disrupt Cholesterol Availability in Castration-Resistant Prostate Cancer.

There have been several studies that have linked elevated scavenger receptor class b type 1 (SR-B1) expression and activity to the development and progression of castration-resistant prostate cancer (CRPC). SR-B1 facilitates the influx of cholesterol to the cell from lipoproteins in systemic circulation. This influx of cholesterol may be important for many cellular functions, including the synthesis of androgens. Castration-resistant prostate cancer tumors can synthesize androgens de novo to supplement the loss of exogenous sources often induced by androgen deprivation therapy. Silencing of SR-B1 may impact the ability of prostate cancer cells, particularly those of the castration-resistant state, to maintain the intracellular supply of androgens by removing a supply of cholesterol. SR-B1 expression is elevated in CRPC models and has been linked to poor survival of patients. The overarching belief has been that cholesterol modulation, through either synthesis or uptake inhibition, will impact essential signaling processes, impeding the proliferation of prostate cancer. The reduction in cellular cholesterol availability can impede prostate cancer proliferation through both decreased steroid synthesis and steroid-independent mechanisms, providing a potential therapeutic target for the treatment of prostate cancer. In this article, we discuss and highlight the work on SR-B1 as a potential novel drug target for CRPC management.

Structural overview of macromolecular machines involved in ribosome biogenesis.

The production of ribosomes is essential for ensuring the translational capacity of cells. Because of its high energy demand ribosome production is subject to stringent cellular controls. Hundreds of ribosome assembly factors are required to facilitate assembly of nascent ribosome particles with high fidelity. Many ribosome assembly factors organize into macromolecular machines that drive complex steps of the production pathway. Recent advances in structural biology, in particular cryo-EM, have provided detailed information about the structure and function of these higher order enzymatic assemblies. Here, we summarize recent structures revealing molecular insight into these macromolecular machines with an emphasis on the interplay between discrete active sites.