Background and PurposeAsthma manifests as a heterogeneous syndrome characterized by airway obstruction, inflammation and hyperresponsiveness (AHR). Although the molecular mechanisms remain unclear, activation of specific PI3K isoforms mediate inflammation and AHR. We aimed to determine whether inhibition of PI3Kδ evokes dilation of airways and to elucidate potential mechanisms.Experimental ApproachHuman precision cut lung slices from non‐asthma donors and primary human airway smooth muscle (HASM) cells from both non‐asthma and asthma donors were utilized. Phosphorylation of Akt, myosin phosphatase target subunit 1 (MYPT1) and myosin light chain (MLC) were assessed in HASM cells following either PI3K inhibitor or siRNA treatment. HASM relaxation was assessed by micro‐pattern deformation. Reversal of constriction of airways was assessed following stimulation with PI3K or ROCK inhibitors.Key ResultsSoluble inhibitors or PI3Kδ knockdown reversed carbachol‐induced constriction of human airways, relaxed agonist‐contracted HASM and inhibited pAkt, pMYPT1 and pMLC in HASM. Similarly, inhibition of Rho kinase also dilated human PCLS airways and suppressed pMYPT1 and pMLC. Baseline pMYPT1 was significantly elevated in HASM cells derived from asthma donors in comparison with non‐asthma donors. After desensitization of the β2‐adrenoceptors, a PI3Kδ inhibitor remained an effective dilator. In the presence of IL‐13, dilation by a β agonist, but not PI3K inhibitor, was attenuated.Conclusion and ImplicationsPI3Kδ inhibitors act as dilators of human small airways. Taken together, these findings provide alternative approaches to the clinical management of airway obstruction in asthma.

Overexploitation has directly, negatively affected marine fish populations in the past half-century, modifying not only their abundance but their behaviour and life-history traits. The recovery and resilience of such populations is dependent upon their exploitation history, which often extends back millennia. Hence, data on when exploitation intensified and how populations were composed in historical periods, have the potential to reveal long-term population dynamics and provide context on the baselines currently used in fisheries management and conservation. Here, we setup a framework for investigations on the exploitation history of Atlantic bluefin tuna (Thunnus thynnus; BFT) in the eastern Atlantic and Mediterranean by collating records of their zooarchaeological remains and critically reviewing these alongside the literature. Then, we outline how novel multidisciplinary applications on BFT remains may be used to document long-term population dynamics. Our review of literature provides clear evidence of BFT overexploitation during the mid-20th century ce. Furthermore, a strong case could be made that the intensification of BFT exploitation extends back further to at least the 19th century ce, if not the 13th–16th century ce, in the eastern Atlantic and Mediterranean. However, a host of archaeological evidence would suggest that BFT exploitation may have been intensive since antiquity. Altogether, this indicates that by the currently used management baselines of the 1970s,  population abundance and complexity was already likely to have declined from historical levels, and we identify how biomolecular and morphometric analyses of BFT remains have the potential to further investigate this.

As a result of ocean warming, the species composition of the Arctic seas has begun to shift in a boreal direction. One ecosystem prone to fauna shifts is the Northeast Greenland shelf. The dispersal route taken by boreal fauna to this area is, however, not known. This knowledge is essential to predict to what extent boreal biota will colonise Arctic habitats. Using population genetics, we show that Atlantic cod ( Gadus morhua ), beaked redfish ( Sebastes mentella ), and deep-sea shrimp ( Pandalus borealis ) recently found on the Northeast Greenland shelf originate from the Barents Sea, and suggest that pelagic offspring were dispersed via advection across the Fram Strait. Our results indicate that boreal invasions of Arctic habitats can be driven by advection, and that the fauna of the Barents Sea can project into adjacent habitats with the potential to colonise putatively isolated Arctic ecosystems such as Northeast Greenland.

Dog domestication is still largely unresolved due to time-gaps in the sampling of regions. Ancient Italian canids are particularly understudied, currently represented by only a few specimens. In the present study, we sampled 27 canid remains from Northern Italy dated between the Late Pleistocene and Bronze Age to assess their genetic variability, and thus add context to dog domestication dynamics. They were targeted at four DNA fragments of the hypervariable region 1 of mitochondrial DNA. A total of 11 samples had good DNA preservation and were used for phylogenetic analyses. The dog samples were assigned to dog haplogroups A, C and D, and a Late Pleistocene wolf was set into wolf haplogroup 2. We present our data in the landscape of ancient and modern dog genetic variability, with a particular focus on the ancient Italian samples published thus far. Our results suggest there is high genetic variability within ancient Italian canids, where close relationships were evident between both a ~24,700 years old Italian canid, and Iberian and Bulgarian ancient dogs. These findings emphasize that disentangling dog domestication dynamics benefits from the analysis of specimens from Southern European regions.

Detecting and measuring a non-Gaussian signature of primordial origin in the density field is a major science goal of nextgeneration galaxy surveys. The signal will permit us to determine primordial physics processes and constrain models of cosmic inflation. While traditional approaches utilise a limited set of statistical summaries of the galaxy distribution to constrain primordial non-Gaussianity, we present a field-level approach by Bayesian forward-modelling the entire three-dimensional galaxy survey. Our method naturally and fully self-consistently exploits the entirety of the large-scale structure, e.g., higherorder statistics, peculiar velocity fields, and scale-dependent galaxy bias, to extract information on the local non-Gaussianity parameter, 𝑓 nl . We demonstrate the performance of our approach through various tests with mock galaxy data emulating relevant features of the SDSS-III/BOSS-like survey, and additional tests with a Stage IV mock data set. These tests reveal that the method infers unbiased values of 𝑓 nl by accurately handling survey geometries, noise, and unknown galaxy biases. We demonstrate that our method can achieve constraints of 𝜎 𝑓 nl ≈ 8.78 for SDSS-III/BOSS-like data, an improvement of a factor ∼ 2.5 over currently published constraints. Tests with next-generation mock data show that significant further improvements are feasible with sufficiently high resolution. Furthermore, the results demonstrate that our method can consistently marginalise all nuisance parameters of the data model. The method further provides an inference of the three-dimensional primordial density field, providing opportunities to explore additional signatures of primordial physics.

Atlantic bluefin tuna (Thunnus thynnus; BFT) is a large (up to 3.3 m in length) pelagic predator which has been exploited throughout the eastern Atlantic and Mediterranean since prehistoric times, as attested by its archeological remains. One key insight derivable from these remains is body size, which can indicate past fishing abilities, the impact of fishing, and past migration behavior. Despite this, there exists no reliable method to estimate the size of BFT found in archeological sites. Here, 13 modern Thunnus spp. skeletons were studied to provide power regression equations that estimate body length from vertebra dimensions. In modern specimens, the majority of BFT vertebrae can be differentiated by their morphological features, and thus, individual regression equations can be applied for each rank (position in vertebral column). In an archeological context, poor preservation may limit one's ability to identify rank; hence, "types" of vertebrae were defined, which enable length estimates when rank cannot be determined. At least one vertebra dimension, height, width, or length correlated highly with body length when vertebrae were ranked (R 2 > 0.97) or identified to types (R 2 > 0.98). Whether using rank or type, length estimates appear accurate to approximately ±10%. Finally, the method was applied to a sample of Roman-era BFT vertebrae to demonstrate its potential. It is acknowledged that further studies with larger sample sizes would provide more precision in BFT length estimates.

Canned tuna is one of the most widely traded seafood products internationally and is of growing demand. There is an increasing concern over the vulnerability of canned tuna supply chains to species mislabelling and fraud. Extensive processing conditions in canning operations can lead to the degradation and fragmentation of DNA, complicating product traceability. We here employed a forensically validated DNA barcoding tool (cytochrome b partial sequences) to assess the effects of canning processes on DNA degradation and the identification of four tropical tuna species (yellowfin, bigeye, skipjack and longtail tuna) collected on a global scale, along their commercial chains. Each species was studied under five different canning processes i.e., freezing, defrosting, cooking, and canning in oil and brine, in order to investigate how these affect DNA-based species identification and traceability. The highest percentage of nucleotide substitutions were observed after brine-canning operations and were greatest for yellowfin and skipjack tuna. Overall, we found that DNA degradation significantly increased along the tuna canning process for most specimens. Consequently, most of the specimens canned in oil or brine were misidentified due to the high rate of nucleotide substitution in diagnostic sequences.

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