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Over the past couple of decades, antibody–drug conjugates (ADCs) have revolutionized the field of cancer chemotherapy. Unlike conventional treatments that damage healthy tissues upon dose escalation, ADCs utilize monoclonal antibodies (mAbs) to specifically bind tumour-associated target antigens and deliver a highly potent cytotoxic agent. The synergistic combination of mAbs conjugated to small-molecule chemotherapeutics, via a stable linker, has given rise to an extremely efficacious class of anti-cancer drugs with an already large and rapidly growing clinical pipeline. The primary objective of this paper is to review current knowledge and latest developments in the field of ADCs. Upon intravenous administration, ADCs bind to their target antigens and are internalized through receptor-mediated endocytosis. This facilitates the subsequent release of the cytotoxin, which eventually leads to apoptotic cell death of the cancer cell. The three components of ADCs (mAb, linker and cytotoxin) affect the efficacy and toxicity of the conjugate. Optimizing each one, while enhancing the functionality of the ADC as a whole, has been one of the major considerations of ADC design and development. In addition to these, the choice of clinically relevant targets and the position and number of linkages have also been the key determinants of ADC efficacy. The only marketed ADCs, brentuximab vedotin and trastuzumab emtansine (T-DM1), have demonstrated their use against both haematological and solid malignancies respectively. The success of future ADCs relies on improving target selection, increasing cytotoxin potency, developing innovative linkers and overcoming drug resistance. As more research is conducted to tackle these issues, ADCs are likely to become part of the future of targeted cancer therapeutics.

Recent studies suggest that alterations in the gut phagobiota may contribute to pathophysiological processes in mammals; however, the association of bacteriophage community structure with Parkinson’s disease (PD) has not been yet characterized. Towards this end, we used a published dataset to analyse bacteriophage composition and determine the phage/bacteria ratio in faecal samples from drug-naive PD patients and healthy participants. Our analyses revealed significant alterations in the representation of certain bacteriophages in the phagobiota of PD patients. We identified shifts of the phage/bacteria ratio in lactic acid bacteria known to produce dopamine and regulate intestinal permeability, which are major factors implicated in PD pathogenesis. Furthermore, we observed the depletion of Lactococcus spp. in the PD group, which was most likely due to the increase of lytic c2-like and 936-like lactococcal phages frequently present in dairy products. Our findings add bacteriophages to the list of possible factors associated with the development of PD, suggesting that gut phagobiota composition may serve as a diagnostic tool as well as a target for therapeutic intervention, which should be confirmed in further studies. Our results open a discussion on the role of environmental phages and phagobiota composition in health and disease.

The etiopathogenesis of type 1 diabetes (T1D), a common autoimmune disorder, is not completely understood. Recent studies suggested the gut microbiome plays a role in T1D. We have used public longitudinal microbiome data from T1D patients to analyze amyloid-producing bacterial composition and found a significant association between initially high amyloid-producing Escherichia coli abundance, subsequent E . coli depletion prior to seroconversion, and T1D development. In children who presented seroconversion or developed T1D, we observed an increase in the E . coli phage/ E . coli ratio prior to E . coli depletion, suggesting that the decrease in E . coli was due to prophage activation. Evaluation of the role of phages in amyloid release from E . coli biofilms in vitro suggested an indirect role of the bacterial phages in the modulation of host immunity. This study for the first time suggests that amyloid-producing E . coli , their phages, and bacteria-derived amyloid might be involved in pro-diabetic pathway activation in children at risk for T1D.

Knowledge of global patterns of biodiversity, ranging from intraspecific genetic diversity (GD) to taxonomic and phylogenetic diversity, is essential for identifying and conserving the processes that shape the distribution of life. Yet, global patterns of GD and its drivers remain elusive. Here we assess existing biodiversity theories to explain and predict the global distribution of GD in terrestrial mammal assemblages. We find a strong positive covariation between GD and interspecific diversity, with evolutionary time, reflected in phylogenetic diversity, being the best predictor of GD. Moreover, we reveal the negative effect of past rapid climate change and the positive effect of inter-annual precipitation variability in shaping GD. Our models, explaining almost half of the variation in GD globally, uncover the importance of deep evolutionary history and past climate stability in accumulating and maintaining intraspecific diversity, and constitute a crucial step towards reducing the Wallacean shortfall for an important dimension of biodiversity. The drivers of genetic diversity (GD) are poorly understood at the global scale. Here the authors show, for terrestrial mammals, that within-species GD covaries with phylogenetic diversity and is higher in locations with more stable past climates. They also interpolate GD for data-poor locations such as the tropics.

SignificanceSr2RuO4 is distinctive among unconventional superconductors, in that in addition to exhibiting evidence for strong correlations, it is stoichiometric and extremely clean. As a result, its electronic structure is unusually well characterized, rendering it an ideal platform for developing a deep understanding of the mechanism behind the emergence of the superconducting state from a Fermi liquid. Toward that end, an unambiguous determination of the pairing symmetry is an essential step. For more than 2 decades, the preponderance of evidence pointed to a triplet spin pairing state and only recently has this interpretation been challenged. By field-dependent NMR Knight shift measurements, we eliminate from further consideration all candidate purely odd-parity triplet pairing states. Unambiguous identification of the superconducting order parameter symmetry in Sr2RuO4 has remained elusive for more than a quarter century. While a chiral p-wave ground state analogue to superfluid 3He-A was ruled out only very recently, other proposed triplet-pairing scenarios are still viable. Establishing the condensate magnetic susceptibility reveals a sharp distinction between even-parity (singlet) and odd-parity (triplet) pairing since the superconducting condensate is magnetically polarizable only in the latter case. Here field-dependent 17O Knight shift measurements, being sensitive to the spin polarization, are compared to previously reported specific heat measurements for the purpose of distinguishing the condensate contribution from that due to quasiparticles. We conclude that the shift results can be accounted for entirely by the expected field-induced quasiparticle response. An upper bound for the condensate magnetic response of <10% of the normal state susceptibility is sufficient to exclude all purely odd-parity candidates.

Aim European colonisation of Australia triggered a cascade of processes that continue to threaten biodiversity today. These include the introduction of invasive species, responsible for rapid and widescale extinctions. Here, we integrated process‐based models with thousands of first sighting records to reconstruct the arrival and spread of European red foxes (Vulpes vulpes) in Australia at a high spatiotemporal resolution. Location: Continental Australia. Methods We constructed tens of thousands of spatially explicit population models of fox colonisation dynamics, using historical records, demographic estimates and spatiotemporal patterns of climate and environmental change. We then tested model outputs against inferences of timings of fox arrival from newspaper articles and empirical estimates of population sizes. Results We show that it took just 60 years for foxes to infill their entire potential distribution of Australia. Foxes colonised mesic regions of Australia earlier than the more arid regions of central and north‐western Australia, reaching carrying capacity shortly after the middle of the 20th century. Conclusions These new insights into the temporal pattern of spread of foxes across Australia, its underpinning processes, and associated maps of abundances promise to help better explain past losses of biodiversity, providing critical information needed to avert future extinctions of Australia's unique fauna. Our process‐based approach for projecting invasion histories should prove similarly useful for reconstructing the biogeography of other invasive species, including cryptic populations at the early stages of invasion.

The ability of bacteria to sense specific molecules within their environment and trigger metabolic responses in accordance is an invaluable biotechnological resource. While many transcription factors (TFs) mediating such processes have been studied, only a handful have been leveraged for molecular biology applications. To expand the repertoire of biotechnologically relevant sensors we present a strategy for the construction and testing of chimeric TF libraries, based on the fusion of highly soluble periplasmic binding proteins (PBPs) with DNA-binding domains (DBDs). We validate this concept by constructing and functionally testing two unique sense-and-respond regulators for benzoate, an environmentally and industrially relevant metabolite. This work will enable the development of tailored biosensors for novel synthetic regulatory circuits. Bacterially encoded environmental sensor proteins are potentially a rich source of transcriptional control but only a few have been harnessed for biotechnological applications. Here the authors develop a general strategy for designing custom-made monogenic synthetic sensors and validate the approach by designing two sense-and-respond regulators for benzoate.

Climate stability leads to high levels of speciation and reduced extinction rates, shaping species richness patterns1–3. Hotspots of species diversity often overlap with regions that experienced stable temperatures and, perhaps, variable rates of precipitation during the late Quaternary4,5. These hotspots potentially harbour many species with low vagility and small geographical ranges6, making them more vulnerable to future ecoclimatic change4,7,8. By comparing global and regional patterns of climate stability during short periods of unusually large and widespread climate changes since the Last Glacial Maximum with twenty-first-century patterns, we show that human-driven climate change will disproportionally affect biodiversity in late Quaternary climate refugia, ultimately affecting the species, communities and ecosystems that are most vulnerable to climate change. Moreover, future changes in absolute temperature will probably erode the mechanisms that are theorized to sustain biodiversity hotspots across time. These impending shifts from stable to unstable temperatures—projected for the majority of the world’s biodiversity regions—threaten to reduce the size and extent of important climatic safe havens for diversity. Where climate refugia are forecast to persist until the end of this century, temperatures in these refuges are likely to exceed the acclimation capacity of many species, making them short-term hospices for biodiversity at best7–9.The stability of climatic conditions since the Last Glacial Maximum has contributed to current global patterns of species richness. Changes in patterns of climate stability this century reveal areas where climate change could reduce biodiversity, with largest losses in past climatic safe havens.

Amphidynamic crystals are an emergent class of condensed phase matter designed with a combination of lattice-forming elements linked to components that display engineered dynamics in the solid state. Here, we address the design of a crystalline array of molecular rotors with inertial diffusional rotation at the nanoscale, characterized by the absence of steric or electronic barriers. We solved this challenge with 1,4-bicyclo[2.2.2]octane dicarboxylic acid (BODCA)-MOF, a metal-organic framework (MOF) built with a high-symmetry bicyclo[2.2.2]octane dicarboxylate linker in a Zn₄O cubic lattice. Using spin-lattice relaxation ¹H solid-state NMR at 29.49 and 13.87 MHz in the temperature range of 2.3–80 K, we showed that internal rotation occurs in a potential with energy barriers of 0.185 kcal mol−1. These results were confirmed with ²H solid-state NMR line-shape analysis and spin-lattice relaxation at 76.78 MHz obtained between 6 and 298 K, which, combined with molecular dynamics simulations, indicate that inertial diffusional rotation is characterized by a broad range of angular displacements with no residence time at any given site. The ambient temperature rotation of the bicyclo[2.2.2]octane (BCO) group in BODCA-MOF constitutes an example where engineered rotational dynamics in the solid state are as fast as they would be in a high-density gas or in a low-density liquid phase.