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In the limnetic zones of small, highly productive reservoirs, young-of-year (YOY) gizzard shad (Dorosoma cepedianum) or threadfin shad (D. petenense) (henceforth, shad) often attain high densities during spring. Environmental factors facilitating early growth and survival of shad plus potential interspecific competition for zooplankton may reduce growth and survival of YOY bluegill (Lepomis macrochirus), another common species in reservoirs. We hypothesized that fewer YOY bluegill moving from the limnetic zone to the littoral zone in late spring probably slows or prevents the ontogenetic switch to piscivory by YOY largemouth bass (Micropterus salmoides), reducing their oversummer growth, overwinter survival, and hence recruitment to their second year. To determine whether shad and bluegill abundances indeed vary inversely in reservoirs, we quantified densities of YOY shad and bluegill in four reservoirs across several years (1987-1994; N = 22 reservoir-years). To assess how YOY bluegill abundance influenced the ontogenetic dietary switch to fish by largemouth bass, we conducted experiments with differing levels of realism and control (4-m2littoral cages, 4.5-m2outdoor pools, and 0.33-m2laboratory aquaria). In reservoirs, peak YOY bluegill density declined weakly in the limnetic zone but strongly in the littoral zone when peak limnetic YOY Dorosoma spp. exceeded 10 individuals/m3. In pools and aquaria, largemouth bass grew more rapidly at ≥3 than at zero bluegill per largemouth bass. Using known temperatures and largemouth bass growth in a bioenergetics model, we discovered that YOY largemouth bass in pools and aquaria ate ≤65% of their maximum daily consumption potential (in grams of wet mass) at ≥6 bluegill per largemouth bass. In cages, largemouth bass consumed only 40% of their maximum and grew less at bluegill abundances similar to those in pools and aquaria, probably because dense vegetation and depletion of bluegill inhibited predatory success. In reservoirs with abundant shad, reduced littoral bluegill density likely compromises first-year growth and recruitment of largemouth bass. However, variable abiotic and biotic factors may modify YOY bluegill abundance and hence invalidate our predictions for largemouth bass recruitment success. To better predict fish community structure and develop management actions for reservoir ecosystems, multi-scale experimentation should be combined with whole-system manipulations (e.g., via adaptive management) to bound these variable interactions.

Though young-of-year (YOY) saugeyes (Stizostedion vitreum x S. canadense) are routinely stocked in spring to create and maintain percid fisheries, their growth and survival to fall vary greatly among Ohio reservoirs, as well as among years within a reservoir. To understand the relative importance of size-dependent and size-independent mechanisms during ontogeny that underlie variable stocking success of saugeye, we quantified the role of stocking date and prey density (zooplankton and ichthyoplankton, i.e., larval gizzard shad [Dorosoma cepedianum]) in field enclosure, pond, and reservoir experiments. In 1-m3enclosures, ichthyoplankton density (0, 5, 10, or 20 larval gizzard shad/m3) did not influence time to switch to piscivory by saugeye (all switched in <12 h); saugeye in enclosures with ichthyoplankton, regardless of density, grew faster than those without ichthyoplankton. In 0.4-ha ponds, saugeye growth and survival did not differ between ponds with zooplankton plus macrobenthic prey and ponds with those prey plus small ichthyoplankton (<10 mm). In reservoir experiments, we evaluated how time in reservoirs, zooplankton density, and peak density (as well as date) of ichthyoplankton influenced saugeye growth and survival during 1991-1994 (N = 31 reservoir-years). In 1993, we attempted to bracket the ichthyoplankton peak in five Ohio reservoirs by stocking two genetically identifiable cohorts of saugeye 2 wk apart in spring. For all reservoirs, those saugeye stocked before the ichthyoplankton peak grew larger than those stocked after the ichthyoplankton peak by 1 October. In 1994, we hypothesized that saugeye might overexploit local populations of ichthyoplankton when stocked at a single site. We paired 10 reservoirs (N = 5 pairs) with one reservoir of each pair scatter-stocked (i.e., saugeye numbers equally divided among five sites) and the second point stocked (i.e., at a single site). Stocking method did not influence saugeye survival; late gizzard shad spawning, coupled with low larval densities, yielded poor saugeye survival in 1994. However, YOY saugeye were considerably larger in fall 1994 than in fall 1993, when gizzard shad appeared earlier and produced more larvae. Zooplankton density at stocking influenced neither growth nor survival. Increased time in reservoirs increased fall size but did not influence survival. Although saugeye growth and survival during their first year were unrelated, both measures of stocking success critically depended on gizzard shad availability. Across all years, saugeyes stocked before ichthyoplankton peaks were large (as a result of their ability to consume fast-growing gizzard shad through summer), but survived poorly to fall (perhaps owing to early, high predatory mortality). Conversely, saugeyes stocked after ichthyoplankton peaks were small in fall (for they were unable to exploit large gizzard shad) but survived better (perhaps because gizzard shad provided a predatory buffer). By manipulating stock date relative to ichthyoplankton peaks, fisheries managers can either increase saugeye size or survival to fall, but not both.

The investigational drugs E7820, indisulam and tasisulam (aryl-sulfonamides) promote the degradation of the splicing factor RBM39 in a proteasome-dependent mechanism. While the activity critically depends on the cullin RING ligase substrate receptor DCAF15, the molecular details remain elusive. Here we present the cryo-EM structure of the DDB1–DCAF15–DDA1 core ligase complex bound to RBM39 and E7820 at a resolution of 4.4 Å, together with crystal structures of engineered subcomplexes. We show that DCAF15 adopts a new fold stabilized by DDA1, and that extensive protein–protein contacts between the ligase and substrate mitigate low affinity interactions between aryl-sulfonamides and DCAF15. Our data demonstrate how aryl-sulfonamides neo-functionalize a shallow, non-conserved pocket on DCAF15 to selectively bind and degrade RBM39 and the closely related splicing factor RBM23 without the requirement for a high-affinity ligand, which has broad implications for the de novo discovery of molecular glue degraders. Cryo-EM and crystal structural analysis of DDB1–DCAF15–DDA1 in complex with E7820 and RBM39 reveal that aryl-sulfonamides reshape the surface of the cullin RING ligase substrate receptor DCAF15 to bind and degrade the splicing factor RBM39.

ObjectivesLipid mediators in the GI tract regulate satiation and satiety. Bile acids (BAs) regulate the absorption and metabolism of dietary lipid in the intestine, but their effects on lipid-regulated satiation and satiety are completely unknown. Investigating this is challenging because introducing excessive BAs or eliminating BAs strongly impacts GI functions. We used a mouse model (Cyp8b1–/– mice) with normal total BA levels, but alterations in the composition of the BA pool that impact multiple aspects of intestinal lipid metabolism. We tested two hypotheses: BAs affect food intake by (1) regulating production of the bioactive lipid oleoylethanolamide (OEA), which enhances satiety; or (2) regulating the quantity and localisation of hydrolysed fat in small intestine, which controls gastric emptying and satiation.DesignWe evaluated OEA levels, gastric emptying and food intake in wild-type and Cyp8b1–/– mice. We assessed the role of the fat receptor GPR119 in these effects using Gpr119–/– mice.ResultsCyp8b1–/– mice on a chow diet showed mild hypophagia. Jejunal OEA production was blunted in Cyp8b1–/– mice, thus these data do not support a role for this pathway in the hypophagia of Cyp8b1–/– mice. On the other hand, Cyp8b1 deficiency decreased gastric emptying, and this was dependent on dietary fat. GPR119 deficiency normalised the gastric emptying, gut hormone levels, food intake and body weight of Cyp8b1–/– mice.ConclusionBAs regulate gastric emptying and satiation by determining fat-dependent GPR119 activity in distal intestine.

Targeted protein degradation is a promising drug development paradigm. Here we leverage this strategy to develop a new class of small molecule antivirals that induce proteasomal degradation of viral proteins. Telaprevir, a reversible-covalent inhibitor that binds to the hepatitis C virus (HCV) protease active site is conjugated to ligands that recruit the CRL4 CRBN ligase complex, yielding compounds that can both inhibit and induce the degradation of the HCV NS3/4A protease. An optimized degrader, DGY-08-097, potently inhibits HCV in a cellular infection model, and we demonstrate that protein degradation contributes to its antiviral activity. Finally, we show that this new class of antiviral agents can overcome viral variants that confer resistance to traditional enzymatic inhibitors such as telaprevir. Overall, our work provides proof-of-concept that targeted protein degradation may provide a new paradigm for the development of antivirals with superior resistance profiles. Targeted protein degradation (TPD) is a promising strategy for drug development. In this proof-of-concept study, the authors use telaprevir, which binds hepatitis C virus (HCV) NS3/4A protease, to target the protease for protein degradation, and show inhibition of wildtype as well as drug resistant HCV.

The selective allosteric ABL1 inhibitor ABL001 (asciminib) represents a new inhibitory mechanism for BCR–ABL1-driven malignancies, and its efficacy and evolving mechanisms of resistance do not overlap with those of other BCR–ABL1 kinase inhibitors. Dual targeting of gene fusion Current inhibitors targeting the BCR–ABL1 mutation have saved many lives but their application is limited by resistance-driving mutations. Here, the authors report the characterization of ABL001, a new allosteric ABL inhibitor. The compound represents a new inhibitory enzymatic mechanism for BCR–ABL-driven malignancies and could be applied for cases of resistance. The authors note that its efficacy and evolving mechanisms of resistance do not overlap with other BCR–ABL kinase inhibitors. Chronic myeloid leukaemia (CML) is driven by the activity of the BCR–ABL1 fusion oncoprotein. ABL1 kinase inhibitors have improved the clinical outcomes for patients with CML, with over 80% of patients treated with imatinib surviving for more than 10 years 1 . Second-generation ABL1 kinase inhibitors induce more potent molecular responses in both previously untreated and imatinib-resistant patients with CML 2 . Studies in patients with chronic-phase CML have shown that around 50% of patients who achieve and maintain undetectable BCR–ABL1 transcript levels for at least 2 years remain disease-free after the withdrawal of treatment 3 , 4 . Here we characterize ABL001 (asciminib), a potent and selective allosteric ABL1 inhibitor that is undergoing clinical development testing in patients with CML and Philadelphia chromosome-positive (Ph + ) acute lymphoblastic leukaemia. In contrast to catalytic-site ABL1 kinase inhibitors, ABL001 binds to the myristoyl pocket of ABL1 and induces the formation of an inactive kinase conformation. ABL001 and second-generation catalytic inhibitors have similar cellular potencies but distinct patterns of resistance mutations, with genetic barcoding studies revealing pre-existing clonal populations with no shared resistance between ABL001 and the catalytic inhibitor nilotinib. Consistent with this profile, acquired resistance was observed with single-agent therapy in mice; however, the combination of ABL001 and nilotinib led to complete disease control and eradicated CML xenograft tumours without recurrence after the cessation of treatment.

Coral reefs worldwide face unprecedented cumulative anthropogenic effects of interacting local human pressures, global climate change and distal social processes. Reefs are also bound by the natural biophysical environment within which they exist. In this context, a key challenge for effective management is understanding how anthropogenic and biophysical conditions interact to drive distinct coral reef configurations. Here, we use machine learning to conduct explanatory predictions on reef ecosystems defined by both fish and benthic communities. Drawing on the most spatially extensive dataset available across the Hawaiian archipelago—20 anthropogenic and biophysical predictors over 620 survey sites—we model the occurrence of four distinct reef regimes and provide a novel approach to quantify the relative influence of human and environmental variables in shaping reef ecosystems. Our findings highlight the nuances of what underpins different coral reef regimes, the overwhelming importance of biophysical predictors and how a reef's natural setting may either expand or narrow the opportunity space for management interventions. The methods developed through this study can help inform reef practitioners and hold promises for replication across a broad range of ecosystems.

The zinc-finger transcription factor Helios is critical for maintaining the identity, anergic phenotype and suppressive activity of regulatory T (T reg ) cells. While it is an attractive target to enhance the efficacy of currently approved immunotherapies, no existing approaches can directly modulate Helios activity or abundance. Here, we report the structure-guided development of small molecules that recruit the E3 ubiquitin ligase substrate receptor cereblon to Helios, thereby promoting its degradation. Pharmacological Helios degradation destabilized the anergic phenotype and reduced the suppressive activity of T reg cells, establishing a route towards Helios-targeting therapeutics. More generally, this study provides a framework for the development of small-molecule degraders for previously unligandable targets by reprogramming E3 ligase substrate specificity. Two degraders targeting zinc finger transcription factor IKZF2 (Helios) were developed by reprogramming CRL4 CRBN E3 ligase, and the pharmacologic degradation of Helios results in T reg destabilization.

In recent years, considerable advances have been made in the characterization of protein-coding alterations involved in the pathogenesis of melanoma. However, despite their growing implication in cancer, little is known about the role of long noncoding RNAs in melanoma progression. We hypothesized that copy number alterations (CNAs) of intergenic nonprotein-coding domains could help identify long intergenic noncoding RNAs (lincRNAs) associated with metastatic cutaneous melanoma. Among several candidates, our approach uncovered the chromosome 6p22.3 CASC15 (cancer susceptibility candidate 15) lincRNA locus as a frequently gained genomic segment in metastatic melanoma tumors and cell lines. The locus was actively transcribed in metastatic melanoma cells, and upregulation of CASC15 expression was associated with metastatic progression to brain metastasis in a mouse xenograft model. In clinical specimens, CASC15 levels increased during melanoma progression and were independent predictors of disease recurrence in a cohort of 141 patients with AJCC (American Joint Committee on Cancer) stage III lymph node metastasis. Moreover, small interfering RNA (siRNA) knockdown experiments revealed that CASC15 regulates melanoma cell phenotype switching between proliferative and invasive states. Accordingly, CASC15 levels correlated with known gene signatures corresponding to melanoma proliferative and invasive phenotypes. These findings support a key role for CASC15 in metastatic melanoma.