Even cooler insights: On the power of forests to (water the Earth and) cool the planet.

Scientific innovation is overturning conventional paradigms of forest, water, and energy cycle interactions. This has implications for our understanding of the principal causal pathways by which tree, forest, and vegetation cover (TFVC) influence local and global warming/cooling. Many identify surface albedo and carbon sequestration as the principal causal pathways by which TFVC affects global warming/cooling. Moving toward the outer latitudes, in particular, where snow cover is more important, surface albedo effects are perceived to overpower carbon sequestration. By raising surface albedo, deforestation is thus predicted to lead to surface cooling, while increasing forest cover is assumed to result in warming. Observational data, however, generally support the opposite conclusion, suggesting surface albedo is poorly understood. Most accept that surface temperatures are influenced by the interplay of surface albedo, incoming shortwave (SW) radiation, and the partitioning of the remaining, post-albedo, SW radiation into latent and sensible heat. However, the extent to which the avoidance of sensible heat formation is first and foremost mediated by the presence (absence) of water and TFVC is not well understood. TFVC both mediates the availability of water on the land surface and drives the potential for latent heat production (evapotranspiration, ET). While latent heat is more directly linked to local than global cooling/warming, it is driven by photosynthesis and carbon sequestration and powers additional cloud formation and top-of-cloud reflectivity, both of which drive global cooling. TFVC loss reduces water storage, precipitation recycling, and downwind rainfall potential, thus driving the reduction of both ET (latent heat) and cloud formation. By reducing latent heat, cloud formation, and precipitation, deforestation thus powers warming (sensible heat formation), which further diminishes TFVC growth (carbon sequestration). Large-scale tree and forest restoration could, therefore, contribute significantly to both global and surface temperature cooling through the principal causal pathways of carbon sequestration and cloud formation.

OSWG Recommended Approaches to the Nonclinical Pharmacokinetic (ADME) Characterization of Therapeutic Oligonucleotides.

This white paper summarizes the recommendations of the absorption, distribution, metabolism, and excretion (ADME) Subcommittee of the Oligonucleotide Safety Working Group for the characterization of absorption, distribution, metabolism, and excretion of oligonucleotide (ON) therapeutics in nonclinical studies. In general, the recommended approach is similar to that for small molecule drugs. However, some differences in timing and/or scope may be warranted due to the greater consistency of results across ON classes as compared with the diversity among small molecule classes. For some types of studies, a platform-based approach may be appropriate; once sufficient data are available for the platform, presentation of these data should be sufficient to support development of additional ONs of the same platform. These recommendations can serve as a starting point for nonclinical study design and foundation for discussions with regulatory agencies.

Constrained future brightening of solar radiation and its implication for China's solar power.

As Earth's primary energy source, surface downward solar radiation (R s) determines the solar power potential and usage for climate change mitigation. Future projections of R s based on climate models have large uncertainties that interfere with the efficient deployment of solar energy to achieve China's carbon-neutrality goal. Here we assess 24 models in the latest Coupled Model Intercomparison Project Phase 6 with historical observations in China and find systematic biases in simulating historical R s values likely due to model biases in cloud cover and clear-sky radiation, resulting in largely uncertain projections for future changes in R s. Based on emergent constraints, we obtain credible R s with narrowed uncertainties by ∼56% in the mid-twenty-first century and show that the mean R s change during 2050-2069 relative to 1995-2014 is 30% more brightening than the raw projections. Particularly in North China and Southeast China with higher power demand, the constrained projections present more significant brightening, highlighting the importance of considering the spatial changes in future Rs when locating new solar energy infrastructures.

Vegetation type is an important predictor of the arctic summer land surface energy budget.

Despite the importance of high-latitude surface energy budgets (SEBs) for land-climate interactions in the rapidly changing Arctic, uncertainties in their prediction persist. Here, we harmonize SEB observations across a network of vegetated and glaciated sites at circumpolar scale (1994-2021). Our variance-partitioning analysis identifies vegetation type as an important predictor for SEB-components during Arctic summer (June-August), compared to other SEB-drivers including climate, latitude and permafrost characteristics. Differences among vegetation types can be of similar magnitude as between vegetation and glacier surfaces and are especially high for summer sensible and latent heat fluxes. The timing of SEB-flux summer-regimes (when daily mean values exceed 0 Wm-2) relative to snow-free and -onset dates varies substantially depending on vegetation type, implying vegetation controls on snow-cover and SEB-flux seasonality. Our results indicate complex shifts in surface energy fluxes with land-cover transitions and a lengthening summer season, and highlight the potential for improving future Earth system models via a refined representation of Arctic vegetation types.

Physiologically Based Pharmacokinetic Modeling for Selumetinib to Evaluate Drug-Drug Interactions and Pediatric Dose Regimens.

Selumetinib (ARRY-142886), an oral, potent and highly selective allosteric mitogen-activated protein kinase kinase 1/2 inhibitor, is approved by the US Food and Drug Administration for the treatment of pediatric patients aged ≥2 years with neurofibromatosis type 1 with symptomatic, inoperable plexiform neurofibromas. A physiologically based pharmacokinetic (PBPK) model was constructed to predict plasma concentration-time profiles of selumetinib, and to evaluate the impact of coadministering moderate cytochrome P450 (CYP) 3A4/2C19 inhibitors/inducers. The model was also used to extrapolate pharmacokinetic exposures from older children with different body surface area to guide dosing in younger children. This model was built based on physiochemical data and clinical in vivo drug-drug interaction (DDI) studies with itraconazole and fluconazole, and verified against data from an in vivo rifampicin DDI study and an absolute bioavailability study. The pediatric model was updated by changing system-specific input parameters using the Simcyp pediatric module. The model captured the observed selumetinib pharmacokinetic profiles and the interactions with CYP inhibitors/inducers. The predictions from the PBPK model showed a DDI effect of 30% to 40% increase or decrease in selumetinib exposure when coadministered with moderate CYP inhibitors or inducers, respectively, which was used to inform dose management and adjustments. The pediatric PBPK model was applied to simulate exposures in specific body surface area brackets that matched those achieved with a 25 mg/m2 dose in SPRINT clinical trials. The pediatric PBPK model was used to guide the dose for younger patients in a planned pediatric clinical study.

Design and optimisation of dendrimer-conjugated Bcl-2/xL inhibitor, AZD0466, with improved therapeutic index for cancer therapy.

Dual Bcl-2/Bcl-xL inhibitors are expected to deliver therapeutic benefit in many haematological and solid malignancies, however, their use is limited by tolerability issues. AZD4320, a potent dual Bcl-2/Bcl-xL inhibitor, has shown good efficacy however had dose limiting cardiovascular toxicity in preclinical species, coupled with challenging physicochemical properties, which prevented its clinical development. Here, we describe the design and development of AZD0466, a drug-dendrimer conjugate, where AZD4320 is chemically conjugated to a PEGylated poly-lysine dendrimer. Mathematical modelling was employed to determine the optimal release rate of the drug from the dendrimer for maximal therapeutic index in terms of preclinical anti-tumour efficacy and cardiovascular tolerability. The optimised candidate is shown to be efficacious and better tolerated in preclinical models compared with AZD4320 alone. The AZD4320-dendrimer conjugate (AZD0466) identified, through mathematical modelling, has resulted in an improved therapeutic index and thus enabled progression of this promising dual Bcl-2/Bcl-xL inhibitor into clinical development.

Ecological and conceptual consequences of Arctic pollution.

Although the effect of pollution on forest health and decline received much attention in the 1980s, it has not been considered to explain the 'Divergence Problem' in dendroclimatology; a decoupling of tree growth from rising air temperatures since the 1970s. Here we use physical and biogeochemical measurements of hundreds of living and dead conifers to reconstruct the impact of heavy industrialisation around Norilsk in northern Siberia. Moreover, we develop a forward model with surface irradiance forcing to quantify long-distance effects of anthropogenic emissions on the functioning and productivity of Siberia's taiga. Downwind from the world's most polluted Arctic region, tree mortality rates of up to 100% have destroyed 24,000 km2 boreal forest since the 1960s, coincident with dramatic increases in atmospheric sulphur, copper, and nickel concentrations. In addition to regional ecosystem devastation, we demonstrate how 'Arctic Dimming' can explain the circumpolar 'Divergence Problem', and discuss implications on the terrestrial carbon cycle.

AZD4320, A Dual Inhibitor of Bcl-2 and Bcl-xL, Induces Tumor Regression in Hematologic Cancer Models without Dose-limiting Thrombocytopenia.

PURPOSE: Targeting Bcl-2 family members upregulated in multiple cancers has emerged as an important area of cancer therapeutics. While venetoclax, a Bcl-2-selective inhibitor, has had success in the clinic, another family member, Bcl-xL, has also emerged as an important target and as a mechanism of resistance. Therefore, we developed a dual Bcl-2/Bcl-xL inhibitor that broadens the therapeutic activity while minimizing Bcl-xL-mediated thrombocytopenia. EXPERIMENTAL DESIGN: We used structure-based chemistry to design a small-molecule inhibitor of Bcl-2 and Bcl-xL and assessed the activity against in vitro cell lines, patient samples, and in vivo models. We applied pharmacokinetic/pharmacodynamic (PK/PD) modeling to integrate our understanding of on-target activity of the dual inhibitor in tumors and platelets across dose levels and over time. RESULTS: We discovered AZD4320, which has nanomolar affinity for Bcl-2 and Bcl-xL, and mechanistically drives cell death through the mitochondrial apoptotic pathway. AZD4320 demonstrates activity in both Bcl-2- and Bcl-xL-dependent hematologic cancer cell lines and enhanced activity in acute myeloid leukemia (AML) patient samples compared with the Bcl-2-selective agent venetoclax. A single intravenous bolus dose of AZD4320 induces tumor regression with transient thrombocytopenia, which recovers in less than a week, suggesting a clinical weekly schedule would enable targeting of Bcl-2/Bcl-xL-dependent tumors without incurring dose-limiting thrombocytopenia. AZD4320 demonstrates monotherapy activity in patient-derived AML and venetoclax-resistant xenograft models. CONCLUSIONS: AZD4320 is a potent molecule with manageable thrombocytopenia risk to explore the utility of a dual Bcl-2/Bcl-xL inhibitor across a broad range of tumor types with dysregulation of Bcl-2 prosurvival proteins.

Incidental diagnosis of leukocyte adhesion deficiency type II following ABO typing.

Individuals with the Bombay phenotype (Oh) in the ABO blood group system do not express the H, A, and B antigens but have no clinical symptoms. Bombay phenotype with clinical symptoms has been described in leukocyte adhesion deficiency type II (LAD II), a fucosylation disorder caused by mutations in SLC35C1. Only few LAD II patients have been described so far. Here we describe an additional patient, a 22-year old male, born to unrelated parents, presenting with inflammatory skin disease, periodontitis, growth, and mental retardation, admitted to the department of dentistry for treatment under general anesthesia. Pre-operative routine investigations revealed the presence of the Bombay phenotype (Oh). Genomic sequencing identified two novel triplet deletions of the SLC35C1 gene. Functional investigations confirmed the diagnosis of LAD II. Therapy with oral fucose led to the disappearance of the chronic skin infections and improvements in behavior and attention span.

Auditory processing in the zebra finch midbrain: single unit responses and effect of rearing experience.

In birds the auditory system plays a key role in providing the sensory input used to discriminate between conspecific and heterospecific vocal signals. In those species that are known to learn their vocalizations, for example, songbirds, it is generally considered that this ability arises and is manifest in the forebrain, although there is no a priori reason why brainstem components of the auditory system could not also play an important part. To test this assumption, we used groups of normal reared and cross-fostered zebra finches that had previously been shown in behavioural experiments to reduce their preference for conspecific songs subsequent to cross fostering experience with Bengalese finches, a related species with a distinctly different song. The question we asked, therefore, is whether this experiential change also changes the bias in favour of conspecific song displayed by auditory midbrain units of normally raised zebra finches. By recording the responses of single units in MLd to a variety of zebra finch and Bengalese finch songs in both normally reared and cross-fostered zebra finches, we provide a positive answer to this question. That is, the difference in response to conspecific and heterospecific songs seen in normal reared zebra finches is reduced following cross-fostering. In birds the virtual absence of mammalian-like cortical projections upon auditory brainstem nuclei argues against the interpretation that MLd units change, as observed in the present experiments, as a result of top-down influences on sensory processing. Instead, it appears that MLd units can be influenced significantly by sensory inputs arising directly from a change in auditory experience during development.

The global energy balance as represented in CMIP6 climate models.

A plausible simulation of the global energy balance is a first-order requirement for a credible climate model. Here I investigate the representation of the global energy balance in 40 state-of-the-art global climate models participating in the Coupled Model Intercomparison Project phase 6 (CMIP6). In the CMIP6 multi-model mean, the magnitudes of the energy balance components are often in better agreement with recent reference estimates compared to earlier model generations on a global mean basis. However, the inter-model spread in the representation of many of the components remains substantial, often on the order of 10-20 Wm-2 globally, except for aspects of the shortwave clear-sky budgets, which are now more consistently simulated by the CMIP6 models. The substantial inter-model spread in the simulated global mean latent heat fluxes in the CMIP6 models, exceeding 20% (18 Wm-2), further implies also large discrepancies in their representation of the global water balance. From a historic perspective of model development over the past decades, the largest adjustments in the magnitudes of the simulated present-day global mean energy balance components occurred in the shortwave atmospheric clear-sky absorption and the surface downward longwave radiation. Both components were gradually adjusted upwards over several model generations, on the order of 10 Wm-2, to reach 73 and 344 Wm-2, respectively in the CMIP6 multi-model means. Thereby, CMIP6 has become the first model generation that largely remediates long-standing model deficiencies related to an overestimation in surface downward shortwave and compensational underestimation in downward longwave radiation in its multi-model mean.

Radiation dimming and decreasing water clarity fuel underwater darkening in lakes.

Long-term decreases in the incident total radiation and water clarity might substantially affect the underwater light environment in aquatic ecosystems. However, the underlying mechanism and relative contributions of radiation dimming and decreasing water clarity to the underwater light environment on a national or global scale remains largely unknown. Here, we present a comprehensive dataset of unprecedented scale in China's lakes to address the combined effects of radiation dimming and decreasing water clarity on underwater darkening. Long-term total radiation and sunshine duration showed 5.8% and 7.9% decreases, respectively, after 2000 compared to 1961-1970, resulting in net radiation dimming. An in situ Secchi disk depth (SDD) dataset in 170 lakes showed that the mean SDD significantly decreased from 1.80 ± 2.19 m before 1995 to 1.28 ± 1.82 m after 2005. SDD remote sensing estimations for 641 lakes with areas ≥ 10 km2 showed that SDD markedly decreased from 1.26 ± 0.62 m during 1985-1990 to 1.14 ± 0.66 m during 2005-2010. Radiation dimming and decreasing water clarity jointly caused an approximately 10% decrease in the average available photosynthetically active radiation (PAR) in the euphotic layer. Our results revealed a more important role of decreasing water clarity in underwater darkening than radiation dimming. A meta-analysis of long-term SDD observation data from 61 various waters further elucidated a global extensive underwater darkening. Underwater darkening implies a decrease in water quality for potable water supplies, recession in macrophytes and benthic algae, and decreases in benthic primary production, fishery production, and biodiversity.

The cloud-free global energy balance and inferred cloud radiative effects: an assessment based on direct observations and climate models.

In recent studies we quantified the global mean Earth energy balance based on direct observations from surface and space. Here we infer complementary reference estimates for its components specifically under cloud-free conditions. While the clear-sky fluxes at the top of atmosphere (TOA) are accurately known from satellite measurements, the corresponding fluxes at the Earth's surface are not equally well established, as they cannot be directly measured from space. This is also evident in 38 global climate models from CMIP5, which are shown to greatly vary in their clear-sky surface radiation budgets. To better constrain the latter, we established new clear-sky reference climatologies of surface downward shortwave and longwave radiative fluxes from worldwide distributed Baseline Surface Radiation Network sites. 33 out of the 38 CMIP5 models overestimate the clear-sky downward shortwave reference climatologies, whereas both substantial overestimations and underestimations are found in the longwave counterparts in some of the models. From the bias structure of the CMIP5 models we infer best estimates for the global mean surface downward clear-sky shortwave and longwave radiation, at 247 and 314 Wm-2, respectively. With a global mean surface albedo of 13.5% and net shortwave clear-sky flux of 287 Wm-2 at the TOA this results in a global mean clear-sky surface and atmospheric shortwave absorption of 214 and 73 Wm-2, respectively. From the newly-established diagrams of the global energy balance under clear-sky and all-sky conditions, we quantify the cloud radiative effects not only at the TOA, but also within the atmosphere and at the surface.

Fewer clouds in the Mediterranean: consistency of observations and climate simulations.

Clouds play a major role in the climate system, but large uncertainties remain about their decadal variations. Here we report a widespread decrease in cloud cover since the 1970 s over the Mediterranean region, in particular during the 1970 s-1980 s, especially in the central and eastern areas and during springtime. Confidence in these findings is high due to the good agreement between the interannual variations of cloud cover provided by surface observations and several satellite-derived and reanalysis products, although some discrepancies exist in their trends. Climate model simulations of the historical experiment from the Coupled Model Intercomparison Project Phase 5 (CMIP5) also exhibit a decrease in cloud cover over the Mediterranean since the 1970 s, in agreement with surface observations, although the rate of decrease is slightly lower. The observed northward expansion of the Hadley cell is discussed as a possible cause of detected trends.

A novel mutation in PIGW causes glycosylphosphatidylinositol deficiency without hyperphosphatasia.

In recent years, many mutations have been identified that affect the biosynthesis of the glycosylphosphatidylinositol anchor, a biomolecule that attaches surface molecules to cell membranes. Here, we present two second-degree cousins with unexplained patterns of seizures. Next-generation sequencing identified the homozygous c.460A>G; p.(R154G) PIGW mutation in both patients. Transfection of the mutated allele into Pigw-defective CHO cells indicated impaired enzymatic activity of the mutated PIGW product. Alkaline phosphatase did not exceed the upper normal range and flow cytometry of CD16, CD24, and CD66c on granulocytes showed subtle changes of the cellular expression of the glycosylphosphatidylinositol-anchored proteins. The patients' phenotype is therefore remarkably different from the phenotype of the only other described individual with PIGW mutations. Patients might therefore be missed when relying on traditional flow cytometry of glycosylphosphatidylinositol-anchored proteins only and we suggest that glycosylphosphatidylinositol-deficiency should be considered even with patients not showing the typical clinical phenotypes. © 2016 Wiley Periodicals, Inc.

Efficient synthesis of triarylamine-based dyes for p-type dye-sensitized solar cells.

The class of triarylamine-based dyes has proven great potential as efficient light absorbers in inverse (p-type) dye sensitized solar cells (DSSCs). However, detailed investigation and further improvement of p-type DSSCs is strongly hindered by the fact that available synthesis routes of triarylamine-based dyes are inefficient and particularly demanding with regard to time and costs. Here, we report on an efficient synthesis strategy for triarylamine-based dyes for p-type DSSCs. A protocol for the synthesis of the dye-precursor (4-(bis(4-bromophenyl)amino)benzoic acid) is presented along with its X-ray crystal structure. The dye precursor is obtained from the commercially available 4(diphenylamino)benzaldehyde in a yield of 87% and serves as a starting point for the synthesis of various triarylamine-based dyes. Starting from the precursor we further describe a synthesis protocol for the dye 4-{bis[4'-(2,2-dicyanovinyl)-[1,1'-biphenyl]-4-yl]amino}benzoic acid (also known as dye P4) in a yield of 74%. All synthesis steps are characterized by high yields and high purities without the need for laborious purification steps and thus fulfill essential requirements for scale-up.

The impact of climate change on photovoltaic power generation in Europe.

Ambitious climate change mitigation plans call for a significant increase in the use of renewables, which could, however, make the supply system more vulnerable to climate variability and changes. Here we evaluate climate change impacts on solar photovoltaic (PV) power in Europe using the recent EURO-CORDEX ensemble of high-resolution climate projections together with a PV power production model and assuming a well-developed European PV power fleet. Results indicate that the alteration of solar PV supply by the end of this century compared with the estimations made under current climate conditions should be in the range (-14%;+2%), with the largest decreases in Northern countries. Temporal stability of power generation does not appear as strongly affected in future climate scenarios either, even showing a slight positive trend in Southern countries. Therefore, despite small decreases in production expected in some parts of Europe, climate change is unlikely to threaten the European PV sector.

True navigation in migrating gulls requires intact olfactory nerves.

During migratory journeys, birds may become displaced from their normal migratory route. Experimental evidence has shown that adult birds can correct for such displacements and return to their goal. However, the nature of the cues used by migratory birds to perform long distance navigation is still debated. In this experiment we subjected adult lesser black-backed gulls migrating from their Finnish/Russian breeding grounds (from >60°N) to Africa (to < 5°N) to sensory manipulation, to determine the sensory systems required for navigation. We translocated birds westward (1080 km) or eastward (885 km) to simulate natural navigational challenges. When translocated westwards and outside their migratory corridor birds with olfactory nerve section kept a clear directional preference (southerly) but were unable to compensate for the displacement, while intact birds and gulls with the ophthalmic branch of the trigeminal nerve sectioned oriented towards their population-specific migratory corridor. Thus, air-borne olfactory information seems to be important for migrating gulls to navigate successfully in some circumstances.

Optimization of brain penetrant 11ß-hydroxysteroid dehydrogenase type I inhibitors and in vivo testing in diet-induced obese mice.

11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) has been widely considered by the pharmaceutical industry as a target to treat metabolic syndrome in type II diabetics. We hypothesized that central nervous system (CNS) penetration might be required to see efficacy. Starting from a previously reported pyrimidine compound, we removed hydrogen-bond donors to yield 3, which had modest CNS penetration. More significant progress was achieved by changing the core to give 40, which combines good potency and CNS penetration. Compound 40 was dosed to diet-induced obese (DIO) mice and gave excellent target engagement in the liver and high free exposures of drug, both peripherally and in the CNS. However, no body weight reduction or effects on glucose or insulin were observed in this model. Similar data were obtained with a structurally diverse thiazole compound 51. This work casts doubt on the hypothesis that localized tissue modulation of 11ß-HSD1 activity alleviates metabolic syndrome.

Coordinated and unique functions of the E-selectin ligand ESL-1 during inflammatory and hematopoietic recruitment in mice.

Beyond its well-established roles in mediating leukocyte rolling, E-selectin is emerging as a multifunctional receptor capable of inducing integrin activation in neutrophils, and of regulating various biological processes in hematopoietic precursors. Although these effects suggest important homeostatic contributions of this selectin in the immune and hematologic systems, the ligands responsible for transducing these effects in different leukocyte lineages are not well defined. We have characterized mice deficient in E-selectin ligand-1 (ESL-1), or in both P-selectin glycoprotein-1 (PSGL-1) and ESL-1, to explore and compare the contributions of these glycoproteins in immune and hematopoietic cell trafficking. In the steady state, ESL-1 deficiency resulted in a moderate myeloid expansion that became more prominent when both glycoproteins were eliminated. During inflammation, PSGL-1 dominated E-selectin binding, rolling, integrin activation, and extravasation of mature neutrophils, but only the combined deficiency in PSGL-1 and ESL-1 completely abrogated leukocyte recruitment. Surprisingly, we find that the levels of ESL-1 were strongly elevated in hematopoietic progenitor cells. These elevations correlated with a prominent function of ESL-1 for E-selectin binding and for migration of hematopoietic progenitor cells into the bone marrow. Our results uncover dominant roles for ESL-1 in the immature compartment, and a functional shift toward PSGL-1 dependence in mature neutrophils.