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ABSTRACT The bacterium Pseudomonas aeruginosa is an opportunistic pathogen that can cause lung, skin, wound, joint, urinary tract, and eye infections. While P. aeruginosa is known to exhibit a robust competitive response toward other bacterial species, this bacterium is frequently identified in polymicrobial infections where multiple species survive. For example, in prosthetic joint infections, P. aeruginosa can be identified along with other pathogenic bacteria including Staphylococcus aureus, Enterococcus faecalis, and Corynebacterium striatum. Here, we have explored the survival and behavior of such microbes and find that E. faecalis readily survives culturing with P. aeruginosa while other tested species do not. In each of the tested conditions, E. faecalis growth remained unchanged by the presence of P. aeruginosa, indicating a unique mutualistic interaction between the two species. We find that E. faecalis proximity leads P. aeruginosa to attenuate competitive behaviors as exemplified by reduced production of Pseudomonas quinolone signal and pyocyanin. Reduced alkyl quinolones are important to E. faecalis as these will grow in supernatant from a quinolone mutant but not P. aeruginosa wild-type in planktonic culture. The reduced pyocyanin production of P. aeruginosa is attributable to production of ornithine by E. faecalis, which we recapitulate by adding exogenous ornithine to P. aeruginosa monocultures. Similarly, co-culture with an ornithine-deficient strain of E. faecalis leads P. aeruginosa to yield near monoculture amounts of pyocyanin. Here, we directly demonstrate how notorious pathogens such as P. aeruginosa might persist in polymicrobial infections under the influence of metabolites produced by other bacterial species.IMPORTANCEWhile we now appreciate that many infections are polymicrobial, we understand little of the specific actions between a given set of microbes to enable combinatorial survival and pathogenesis. The bacteria Pseudomonas aeruginosa and Enterococcus faecalis are both prevalent pathogens in wound, urinary tract, and bacteremic infections. While P. aeruginosa often kills other species in standard laboratory culture conditions, we present here that E. faecalis can be reliably co-cultured with P. aeruginosa. We specifically detail that ornithine produced by E. faecalis reduces the Pseudomonas quinolone signal response of P. aeruginosa. This reduction of the Pseudomonas quinolone signal response aids E. faecalis growth.

Cancers utilize a simple glycan, Sialic Acid, to engage in metastatic processes via the Sialic acid (Sia) -Selectin pathway. Selectins recognize and bind to sialylated substrates, resulting in adhesion, migration, and extravasation, however, how deviations from the canonical form of Sia regulate binding to Selectin receptors (E, L, and P) on hemopoietic cells resulting in these metastatic processes, remained a gap in knowledge. De-O-acetylated Sias has been recently shown to be an integral substrate to the binding of sialic acid binding proteins. The two proteins responsible for regulating the acetyl functional group on Sia’s C6 tail, are Sialic acid acetylesterase (SIAE) and Sialic acid O acetyltransferase (CASD1). To elucidate the contribution of functional group alterations on Sia, 9-O and 7,9-O-acetylation of Sia was modulated via the use of CRISRP-Cas9 gene editing and with Sialyl Glycan Recognition Probes, to produce either O-acetylated-Sia or de-O-acetylated- Sia, respectively. In vitro experiments revealed that increased cell surface expression of de-O-acetylated- Sia resulted in an increase in Selectin binding, enhanced cell proliferation, and increased migration capabilities both in lung and colon cancer. These results delineate for the first time the mechanistic contribution of de-O-acetylated-Sia to Selectin binding, reinforcing the importance of elucidating functional group alterations on Sia and their contribution. Without accurate identification of which functionalized form of Sia is being utilized to bind to sialic acid binding proteins, we cannot accurately produce glycan therapeutics with the correct specificity and reactivity, thus this work contributes an integral component in the development of promising therapeutic avenues, for example in the realm of enzyme antibody drug conjugates.

Let Lλ denote the linear operator associated with the radially symmetric form of the wave operator ∂t2−Δ+λ together with the side conditions of decay to zero as r=‖x‖→+∞ and T-periodicity in time. Thus Lλω=ωtt−(ωrr+N−1rωr)+λω, when there are N space variables. For δ,R,T>0 let DT,R=(0,T)×(R,+∞) and Lδ2(D) denote the weighted L2 space with weight function exp(δr). It is shown that Lλ is a Fredholm operator from dom(Lλ)⊂L2(D) onto Lδ2(D) with non-negative index depending on λ. If [2πj/T]2

Abstract Currently available quantum processors are dominated by noise, which severely limits their applicability and motivates the search for new physical qubit encodings. In this work, we introduce the inductively shunted transmon, a weakly flux-tunable superconducting qubit that offers charge offset protection for all levels and a 20-fold reduction in flux dispersion compared to the state-of-the-art resulting in a constant coherence over a full flux quantum. The parabolic confinement provided by the inductive shunt as well as the linearity of the geometric superinductor facilitates a high-power readout that resolves quantum jumps with a fidelity and QND-ness of >90% and without the need for a Josephson parametric amplifier. Moreover, the device reveals quantum tunneling physics between the two prepared fluxon ground states with a measured average decay time of up to 3.5 h. In the future, fast time-domain control of the transition matrix elements could offer a new path forward to also achieve full qubit control in the decay-protected fluxon basis.

Abstract Recent quantum technologies have established precise quantum control of various microscopic systems using electromagnetic waves. Interfaces based on cryogenic cavity electro-optic systems are particularly promising, due to the direct interaction between microwave and optical fields in the quantum regime. Quantum optical control of superconducting microwave circuits has been precluded so far due to the weak electro-optical coupling as well as quasi-particles induced by the pump laser. Here we report the coherent control of a superconducting microwave cavity using laser pulses in a multimode electro-optical device at millikelvin temperature with near-unity cooperativity. Both the stationary and instantaneous responses of the microwave and optical modes comply with the coherent electro-optical interaction, and reveal only minuscule amount of excess back-action with an unanticipated time delay. Our demonstration enables wide ranges of applications beyond quantum transductions, from squeezing and quantum non-demolition measurements of microwave fields, to entanglement generation and hybrid quantum networks.

Abstract The ability to control the direction of scattered light is crucial to provide flexibility and scalability for a wide range of on-chip applications, such as integrated photonics, quantum information processing, and nonlinear optics. Tunable directionality can be achieved by applying external magnetic fields that modify optical selection rules, by using nonlinear effects, or interactions with vibrations. However, these approaches are less suitable to control microwave photon propagation inside integrated superconducting quantum devices. Here, we demonstrate on-demand tunable directional scattering based on two periodically modulated transmon qubits coupled to a transmission line at a fixed distance. By changing the relative phase between the modulation tones, we realize unidirectional forward or backward photon scattering. Such an in-situ switchable mirror represents a versatile tool for intra- and inter-chip microwave photonic processors. In the future, a lattice of qubits can be used to realize topological circuits that exhibit strong nonreciprocity or chirality.

Abstract Purpose Despite that early integration of palliative care is recommended in advanced cancer patients, referrals to outpatient specialised palliative care (SPC) frequently occur late. Well-defined referral criteria are still missing. We analysed indicators associated with early (ER) and late referral (LR) to SPC of an high volume outpatient unit of a comprehensive cancer center. Methods Characteristics, laboratory parameters and symptom burden of 281 patients at first SPC referral were analysed. Timing of referral was categorized as early, intermediate and late (> 12, 3–12 and

Abstract Background Up to half of adults with advanced cancer report anxiety or depression symptoms, which can cause avoidance of future planning. We present a study protocol for an innovative, remotely-delivered, acceptance-based, multi-modal palliative care intervention that addresses advance care planning (ACP) and unmet psychological needs commonly experienced by adults with metastatic cancer. Methods A two-armed, prospective randomized controlled trial (RCT) randomizes 240 adults with Stage IV (and select Stage III) solid tumor cancer who report moderate to high anxiety or depression symptoms to either the multi-modal intervention or usual care. The intervention comprises five weekly two-hour group sessions (plus a booster session one month later) delivered via video conferencing, with online self-paced modules and check-ins completed between the group sessions. Intervention content is based on Acceptance and Commitment Therapy (ACT), an acceptance, mindfulness, and values-based model. Participants are recruited from a network of community cancer care clinics, with group sessions led by the network’s oncology clinical social workers. Participants are assessed at baseline, mid-intervention, post-intervention, and 2-month follow-up. The primary outcome is ACP completion; secondary outcomes include anxiety and depression symptoms, fear of dying, and sense of life meaning. Relationships between anxiety/depression symptoms and ACP will be evaluated cross-sectionally and longitudinally and theory-based putative mediators will be examined. Discussion Among adults with advanced cancer in community oncology settings, this RCT will provide evidence regarding the efficacy of the group ACT intervention on ACP and psychosocial outcomes as well as examine the relationship between ACP and anxiety/ depression symptoms. This trial aims to advance palliative care science and inform clinical practice. Trial Registration Clinicaltrials.gov NCT04773639 on February 26, 2021.

Faithful conversion of quantum states between electrical circuits and light requires adding less than one input noise photon during conversion. Here, the authors demonstrate this based on coherent electro-optic upconversion with a transduction efficiency of 15%.

The transcription factor NKX2-1 is a key regulator of lung pathophysiology, but the importance of its binding sites outside of proximal promoter regions is unclear. Here, William Stuart and Iris Fink-Baldauf et al. use CRISPRi to interrogate 19 NKX2-1 binding sites and identify specific sites important for breathing, innate immune defense, and tumorigenesis.

Soil water is a major requirement for biomass production and, therefore, one of the most important factors for agriculture productivity. As agricultural droughts are related to declining soil moisture, this paper examines soil moisture drought in the transboundary Koshi River basin (KRB) in the central Himalayan region. By applying the J2000 hydrological model, daily spatially distributed soil moisture is derived for the entire basin over a 28-year period (1980–2007). A multi-site and multi-variable approach – streamflow data at one station and evapotranspiration data at three stations – was used for the calibration and validation of the J2000 model. In order to identify drought conditions based on the simulated soil moisture, the soil moisture deficit index (SMDI) was then calculated, considering the derivation of actual soil moisture from long-term soil moisture on a weekly timescale. To spatially subdivide the variations in soil moisture, the river basin is partitioned into three distinct geographical regions, namely trans-Himalaya, the mountains, and the plains. Further, the SMDI is aggregated temporally to four seasons – winter, pre-monsoon, monsoon, and post-monsoon – based on wetness and dryness patterns observed in the study area. This has enabled us to look at the magnitude, extent, and duration of soil moisture drought. The results indicated that the J2000 model can simulate the hydrological processes of the basin with good accuracy. Considerable variation in soil moisture was observed in the three physiographic regions and across the four seasons due to high variation in precipitation and temperature conditions. The year 1992 was the driest year and 1998 was the wettest at the basin scale in both magnitude and duration. Similarly, the year 1992 also has the highest number of weeks under drought. Comparing the SMDI with the standardised precipitation index (SPI) suggested that SMDI can reflect a higher variation in drought conditions than SPI. Our results suggested that both the occurrence and severity of droughts have increased in the Koshi River basin over the last 3 decades, especially in the winter and pre-monsoon seasons. The insights provided into the frequency, spatial coverage, and severity of drought conditions can provide valuable contributions towards an improved management of water resources and greater agricultural productivity in the region.

Existing solutions to interface the microwave and optical domains lack either scalability or efficiency. Here, the authors demonstrate a CMOS compatible converter between microwave and optical signals based on silicon an optomechanical device with a total bidirectional transduction efficiency of 1.2% at millikelvin temperatures.

Night-shift workers may develop poor cardiovascular health. Studies about heart rate variability (HRV) metrics could identify risk factors in this population and be used to examine the effectiveness of interventions for optimizing the health of night-shift workers. The purpose of this review was to examine the use of HRV methodologies in studies about night-shift work. Overall, 34 articles met the selection criteria and underwent a methodological critique. The main conclusion across these studies was that night-shift work could increase the sympathetic influences on the variability between heartbeats. In many cases, however, important methodological details were omitted (e.g., the number and duration of electrocardiogram recordings, sampling rates, R–R segment duration, wavelet transform methods). Recommendations include adding measures of disease outcomes, using ≥250 Hz sampling rates and 600-s R–R segments, and measuring sleep and circadian rhythms. With these approaches, researchers can design investigations that identify therapeutic targets for improving the health of night-shift workers. Int J Occup Med Environ Health. 2020;33(4):409–25

Summary: Background: To identify host genetic variants (SNPs) associated with COVID-19 disease severity, a number of genome-wide association studies (GWAS) have been conducted. Since most of the identified variants are located at non-coding regions, such variants are presumed to affect the expression of neighbouring genes, thereby influencing COVID-19 disease severity. However, it remains largely unknown which genes are influenced by such COVID-19 GWAS loci. Methods: CRISPRi (interference)-mediated gene expression analysis was performed to identify genes functionally regulated by COVID-19 GWAS loci by targeting regions near the loci (SNPs) in lung epithelial cell lines. The expression of CRISPRi-identified genes was investigated using COVID-19-contracted human and monkey lung single-nucleus/cell (sn/sc) RNA-seq datasets. Findings: CRISPRi analysis indicated that a region near rs11385942 at chromosome 3p21.31 (locus of highest significance with COVID-19 disease severity at intron 5 of LZTFL1) significantly affected the expression of LZTFL1 (P

River systems that support high biodiversity profiles are conservation priorities worldwide. Understanding river ecosystem thresholds to low-flow conditions is important for the conservation of these systems. While climatic variations are likely to impact the streamflow variability of many river courses into the future, understanding specific river flow dynamics with regard to streamflow variability and aquifer baseflow contributions is central to the implementation of protection strategies. While streamflow is a measurable quantity, baseflow has to be estimated or calculated through the incorporation of hydrogeological variables. In this study, the groundwater components within the J2000 rainfall–runoff model were distributed to provide daily baseflow and streamflow estimates needed for reserve determination. The modelling approach was applied to the RAMSAR-listed Verlorenvlei estuarine lake system on the west coast of South Africa, which is under threat due to agricultural expansion and climatic fluctuations. The sub-catchment consists of four main tributaries, Krom Antonies, Hol, Bergvallei and Kruismans. Of these, Krom Antonies was initially presumed the largest baseflow contributor, but was shown to have significant streamflow variability attributed to the highly conductive nature of the Table Mountain Group sandstones and Quaternary sediments. Instead, Bergvallei was identified as the major contributor of baseflow. Hol was the least susceptible to streamflow fluctuations due to the higher baseflow proportion (56 %) as well as the dominance of less conductive Malmesbury shales that underlie it. The estimated flow exceedance probabilities indicated that during the 2008–2017 wet cycle average lake inflows exceeded the average evaporation demand, although yearly rainfall is twice as variable in comparison to the first wet cycle between 1987 and 1996. During the 1997–2007 dry cycle, average lake inflows are exceeded 85 % of the time by the evaporation demand. The exceedance probabilities estimated here suggest that inflows from the four main tributaries are not enough to support Verlorenvlei, with the evaporation demand of the entire lake being met only 35 % of the time. This highlights the importance of low-occurrence events for filling up Verlorenvlei, allowing for regeneration of lake-supported ecosystems. As climate change drives increased temperatures and rainfall variability, the length of dry cycles is likely to increase into the future and result in the lake drying up more frequently. For this reason, it is important to ensure that water resources are not over-allocated during wet cycles, hindering ecosystem regeneration and prolonging the length of these dry cycle conditions.

Microenvironmental signals produced during development or inflammation stimulate lymphatic endothelial cells to undergo lymphangiogenesis, in which they sprout, proliferate, and migrate to expand the vascular network. Many cell types detect changes in extracellular conditions via primary cilia, microtubule-based cellular protrusions that house specialized membrane receptors and signaling complexes. Primary cilia are critical for receipt of extracellular cues from both ligand-receptor pathways and physical forces such as fluid shear stress. Here, we report the presence of primary cilia on immortalized mouse and primary adult human dermal lymphatic endothelial cells in vitro and on both luminal and abluminal domains of mouse corneal, skin, and mesenteric lymphatic vessels in vivo. The purpose of this study was to determine the effects of disrupting primary cilia on lymphatic vessel patterning during development and inflammation. Intraflagellar transport protein 20 (IFT20) is part of the transport machinery required for ciliary assembly and function. To disrupt primary ciliary signaling, we generated global and lymphatic endothelium-specific IFT20 knockout mouse models and used immunofluorescence microscopy to quantify changes in lymphatic vessel patterning at E16.5 and in adult suture-mediated corneal lymphangiogenesis. Loss of IFT20 during development resulted in edema, increased and more variable lymphatic vessel caliber and branching, as well as red blood cell-filled lymphatics. We used a corneal suture model to determine ciliation status of lymphatic vessels during acute, recurrent, and tumor-associated inflammatory reactions and wound healing. Primary cilia were present on corneal lymphatics during all of the mechanistically distinct lymphatic patterning events of the model and assembled on lymphatic endothelial cells residing at the limbus, stalk, and vessel tip. Lymphatic-specific deletion of IFT20 cell-autonomously exacerbated acute corneal lymphangiogenesis resulting in increased lymphatic vessel density and branching. These data are the first functional studies of primary cilia on lymphatic endothelial cells and reveal a new dimension in regulation of lymphatic vascular biology.

Paracrine signaling in the tissue microenvironment is a central mediator of morphogenesis, and modeling this dynamic intercellular activity in vitro is critical to understanding normal and abnormal development. For example, Sonic Hedgehog (Shh) signaling is a conserved mechanism involved in multiple developmental processes and strongly linked to human birth defects including orofacial clefts of the lip and palate. SHH ligand produced, processed, and secreted from the epithelial ectoderm is shuttled through the extracellular matrix where it binds mesenchymal receptors, establishing a gradient of transcriptional response that drives orofacial morphogenesis. In humans, complex interactions of genetic predispositions and environmental insults acting on diverse molecular targets are thought to underlie orofacial cleft etiology. Consequently, there is a need for tractable in vitro approaches that model this complex cellular and environmental interplay and are sensitive to disruption across the multistep signaling cascade. We developed a microplate-based device that supports an epithelium directly overlaid onto an extracellular matrix-embedded mesenchyme, mimicking the basic tissue architecture of developing orofacial tissues. SHH ligand produced from the epithelium generated a gradient of SHH-driven transcription in the adjacent mesenchyme, recapitulating the gradient of pathway activity observed in vivo. Shh pathway activation was antagonized by small molecule inhibitors of epithelial secretory, extracellular matrix transport, and mesenchymal sensing targets, supporting the use of this approach in high-content chemical screening of the complete Shh pathway. Together, these findings demonstrate a novel and practical microphysiological model with broad utility for investigating epithelial-mesenchymal interactions and environmental signaling disruptions in development.

Sonic hedgehog (Shh) pathway disruption causes craniofacial malformations including orofacial clefts (OFCs) of the lip and palate. In normal craniofacial morphogenesis, Shh signals to multipotent cranial neural crest cells (cNCCs) and was recently discovered to regulate the angiogenic transcriptome, including expression markers of perivascular cells and pericytes. The mural cells of microvasculature, pericytes in the brain and face differentiate from cNCCs, but their role in facial development is not known. Here, we examined microvascular morphogenesis in a mouse model of Shh pathway antagonist-induced cleft lip and the impact of cNCC-specific Shh pathway activation in a cNCC-endothelial cell co-culture system. During cleft pathogenesis in vivo, disrupted microvascular morphogenesis localized with attenuated tissue outgrowth in the medial nasal processes that form the upper lip. In vitro, we found that human umbilical vein endothelial cell (HUVEC) cord formation was not affected by direct Shh pathway perturbation. However, in a co-culture system in which cNCCs directly interact with endothelial cells, cNCC-autonomous Shh pathway activity significantly prolonged endothelial cord network stability. Taken together, these findings support the premise that Shh pathway activation in cNCCs promotes pericyte-like function and microvascular stability. In addition to suggesting a previously unrecognized role for Shh signaling in facial development, these studies also identify perivascular differentiation and microvascular morphogenesis as new focuses for understanding normal and abnormal craniofacial development.

The GRACE satellites provide signals of total terrestrial water storage (TWS) variations over large spatial domains at seasonal to inter-annual timescales. While the GRACE data have been extensively and successfully used to assess spatio-temporal changes in TWS, little effort has been made to quantify the relative contributions of snowpacks, soil moisture, and other components to the integrated TWS signal across northern latitudes, which is essential to gain a better insight into the underlying hydrological processes. Therefore, this study aims to assess which storage component dominates the spatio-temporal patterns of TWS variations in the humid regions of northern mid- to high latitudes.To do so, we constrained a rather parsimonious hydrological model with multiple state-of-the-art Earth observation products including GRACE TWS anomalies, estimates of snow water equivalent, evapotranspiration fluxes, and gridded runoff estimates. The optimized model demonstrates good agreement with observed hydrological spatio-temporal patterns and was used to assess the relative contributions of solid (snowpack) versus liquid (soil moisture, retained water) storage components to total TWS variations. In particular, we analysed whether the same storage component dominates TWS variations at seasonal and inter-annual temporal scales, and whether the dominating component is consistent across small to large spatial scales.Consistent with previous studies, we show that snow dynamics control seasonal TWS variations across all spatial scales in the northern mid- to high latitudes. In contrast, we find that inter-annual variations of TWS are dominated by liquid water storages at all spatial scales. The relative contribution of snow to inter-annual TWS variations, though, increases when the spatial domain over which the storages are averaged becomes larger. This is due to a stronger spatial coherence of snow dynamics that are mainly driven by temperature, as opposed to spatially more heterogeneous liquid water anomalies, that cancel out when averaged over a larger spatial domain. The findings first highlight the effectiveness of our model–data fusion approach that jointly interprets multiple Earth observation data streams with a simple model. Secondly, they reveal that the determinants of TWS variations in snow-affected northern latitudes are scale-dependent. In particular, they seem to be not merely driven by snow variability, but rather are determined by liquid water storages on inter-annual timescales. We conclude that inferred driving mechanisms of TWS cannot simply be transferred from one scale to another, which is of particular relevance for understanding the short- and long-term variability of water resources.

Abstract Background The evolutionarily conserved Sonic Hedgehog (Shh) signaling pathway is essential for embryogenesis and orofacial development. SHH ligand secreted from the surface ectoderm activates pathway activity in the underlying cranial neural crest cell (cNCC)-derived mesenchyme of the developing upper lip and palate. Disruption of Shh signaling causes orofacial clefts, but the biological action of Shh signaling and the full set of Shh target genes that mediate normal and abnormal orofacial morphogenesis have not been described. Results Using comparative transcriptional profiling, we have defined the Shh-regulated genes of the cNCC-derived mesenchyme. Enrichment analysis demonstrated that in cultured cNCCs, Shh-regulated genes are involved in smooth muscle and chondrocyte differentiation, as well as regulation of the Forkhead family of transcription factors, G1/S cell cycle transition, and angiogenesis. Next, this gene set from Shh-activated cNCCs in vitro was compared to the set of genes dysregulated in the facial primordia in vivo during the initial pathogenesis of Shh pathway inhibitor-induced orofacial clefting. Functional gene annotation enrichment analysis of the 112 Shh-regulated genes with concordant expression changes linked Shh signaling to interdependent and unique biological processes including mesenchyme development, cell adhesion, cell proliferation, cell migration, angiogenesis, perivascular cell markers, and orofacial clefting. Conclusions We defined the Shh-regulated transcriptome of the cNCC-derived mesenchyme by comparing the expression signatures of Shh-activated cNCCs in vitro to primordial midfacial tissues exposed to the Shh pathway inhibitor in vivo. In addition to improving our understanding of cNCC biology by determining the identity and possible roles of cNCC-specific Shh target genes, this study presents novel candidate genes whose examination in the context of human orofacial clefting etiology is warranted.

Hydrological droughts are one of the most damaging disasters in terms of economic loss in central Vietnam and other regions of South-east Asia, severely affecting agricultural production and drinking water supply. Their increasing frequency and severity can be attributed to extended dry spells and increasing water abstractions for e.g. irrigation and hydropower development to meet the demand of dynamic socioeconomic development. Based on hydro-climatic data for the period from 1980 to 2013 and reservoir operation data, the impacts of recent hydropower development and other alterations of the hydrological network on downstream streamflow and drought risk were assessed for a mesoscale basin of steep topography in central Vietnam, the Vu Gia Thu Bon (VGTB) River basin. The Just Another Modelling System (JAMS)/J2000 was calibrated for the VGTB River basin to simulate reservoir inflow and the naturalized discharge time series for the downstream gauging stations. The HEC-ResSim reservoir operation model simulated reservoir outflow from eight major hydropower stations as well as the reconstructed streamflow for the main river branches Vu Gia and Thu Bon. Drought duration, severity, and frequency were analysed for different timescales for the naturalized and reconstructed streamflow by applying the daily varying threshold method. Efficiency statistics for both models show good results. A strong impact of reservoir operation on downstream discharge at the daily, monthly, seasonal, and annual scales was detected for four discharge stations relevant for downstream water allocation. We found a stronger hydrological drought risk for the Vu Gia river supplying water to the city of Da Nang and large irrigation systems especially in the dry season. We conclude that the calibrated model set-up provides a valuable tool to quantify the different origins of drought to support cross-sectorial water management and planning in a suitable way to be transferred to similar river basins.

There are two elementary superconducting qubit types that derive directly from the quantum harmonic oscillator. In one, the inductor is replaced by a nonlinear Josephson junction to realize the widely used charge qubits with a compact phase variable and a discrete charge wave function. In the other, the junction is added in parallel, which gives rise to an extended phase variable, continuous wave functions, and a rich energy-level structure due to the loop topology. While the corresponding rf superconducting quantum interference device Hamiltonian was introduced as a quadratic quasi-one-dimensional potential approximation to describe the fluxonium qubit implemented with long Josephson-junction arrays, in this work we implement it directly using a linear superinductor formed by a single uninterrupted aluminum wire. We present a large variety of qubits, all stemming from the same circuit but with drastically different characteristic energy scales. This includes flux and fluxonium qubits but also the recently introduced quasicharge qubit with strongly enhanced zero-point phase fluctuations and a heavily suppressed flux dispersion. The use of a geometric inductor results in high reproducibility of the inductive energy as guaranteed by top-down lithography—a key ingredient for intrinsically protected superconducting qubits.

Nonreciprocal optical elements often require magnetic materials in order to break time-reversal symmetry. Here, Barzanjeh et al. demonstrate a magnetic-free on-chip microwave circulator that utilizes the interference from six electro-mechanical signal paths.

Holoprosencephaly (HPE) is a common and severe human developmental abnormality marked by malformations of the forebrain and face. Although several genetic mutations have been linked to HPE, phenotypic outcomes range dramatically, and most cases cannot be attributed to a specific cause. Gene-environment interaction has been invoked as a premise to explain the etiological complexity of HPE, but identification of interacting factors has been extremely limited. Here, we demonstrate that mutations in Gli2, which encodes a Hedgehog pathway transcription factor, can cause or predispose to HPE depending upon gene dosage. On the C57BL/6J background, homozygous GLI2 loss of function results in the characteristic brain and facial features seen in severe human HPE, including midfacial hypoplasia, hypotelorism and medial forebrain deficiency with loss of ventral neurospecification. Although normally indistinguishable from wild-type littermates, we demonstrate that mice with single-allele Gli2 mutations exhibit increased penetrance and severity of HPE in response to low-dose teratogen exposure. This genetic predisposition is associated with a Gli2 dosage-dependent attenuation of Hedgehog ligand responsiveness at the cellular level. In addition to revealing a causative role for GLI2 in HPE genesis, these studies demonstrate a mechanism by which normally silent genetic and environmental factors can interact to produce severe outcomes. Taken together, these findings provide a framework for the understanding of the extreme phenotypic variability observed in humans carrying GLI2 mutations and a paradigm for reducing the incidence of this morbid birth defect.

Preparation and detection of mechanical objects at the quantum zero-point level has been achieved in both the optical and microwave regimes. Here, the authors develop silicon nitride nanomembranes that are suitable for integrating nanophotonic, nanomechanical and superconducting microwave circuits together.

Microwave photonics lends the advantages of fiber optics to electronic sensing and communication systems. In contrast to nonlinear optics, electro-optic devices so far require classical modulation fields whose variance is dominated by electronic or thermal noise rather than quantum fluctuations. Here we demonstrate bidirectional single-sideband conversion of X band microwave to C band telecom light with a microwave mode occupancy as low as 0.025±0.005 and an added output noise of less than or equal to 0.074 photons. This is facilitated by radiative cooling and a triply resonant ultra-low-loss transducer operating at millikelvin temperatures. The high bandwidth of 10.7MHz and total (internal) photon conversion efficiency of 0.03% (0.67%) combined with the extremely slow heating rate of 1.1 added output noise photons per second for the highest available pump power of 1.48 mW puts near-unity efficiency pulsed quantum transduction within reach. Together with the non-Gaussian resources of superconducting qubits this might provide the practical foundation to extend the range and scope of current quantum networks in analogy to electrical repeaters in classical fiber optic communication.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

ABSTRACT: Objective: Acquired reactive perforating collagenosis is an uncommon skin disease that belongs to a group of dermatologic disorders characterized by transepidermal elimination of dermal material. It is highly associated with systemic disease, primarily diabetes mellitus and dialysis-dependent chronic renal failure.Methods: A 70-year-old female with 20 years of poorly controlled type 2 diabetes mellitus presented with a 6-month history of multiple pruritic erythematous papules and nodules with central hyperkeratosis, involving her right dorsal arm. Histologic examination was consistent with acquired reactive perforating collagenosis. In addition to topical treatment of the disease, the patient was referred to endocrinology for appropriate management of her underlying diabetes mellitus.Results: Ideal treatment should involve both the endocrinologist and dermatologist. Control of the underlying systemic disease, in this case diabetes, as well topical or systemic medications can both help to improve this condition. Our patient re-established care with her endocrinologist who adjusted her medication regimen, resulting in improved hemoglobin A1c values. Our patient additionally benefited from topical betamethasone cream, ammonium lactate, and pimecrolimus application. The combined therapy led to resolution of her pruritic rash.Conclusion: This case highlights the importance of the skin exam by the endocrinologist, as he or she plays a unique role in identifying this rare and difficult-to-treat dermatologic disease. Early detection and prompt referral to a dermatologist are crucial in preventing progression of disease, treating the disease, and improving the patient's quality of life.Abbreviation: ARPC = acquired reactive perforating collagenosis

The contrasting patterns of lake-level fluctuations across the Tibetan Plateau (TP) are indicators of differences in the water balance over the TP. However, little is known about the key hydrological factors controlling this variability. The purpose of this study is to contribute to a more quantitative understanding of these factors for four selected lakes in the southern-central part of the TP: Nam Co and Tangra Yumco (increasing water levels), and Mapam Yumco and Paiku Co (stable or slightly decreasing water levels). We present the results of an integrated approach combining hydrological modeling, atmospheric-model output and remote-sensing data. The J2000g hydrological model was adapted and extended according to the specific characteristics of closed-lake basins on the TP and driven with High Asia Refined analysis (HAR) data at 10 km resolution for the period 2001–2010. Differences in the mean annual water balances among the four basins are primarily related to higher precipitation totals and attributed runoff generation in the Nam Co and Tangra Yumco basins. Precipitation and associated runoff are the main driving forces for inter-annual lake variations. The glacier-meltwater contribution to the total basin runoff volume (between 14 and 30 % averaged over the 10-year period) plays a less important role compared to runoff generation from rainfall and snowmelt in non-glacierized land areas. Nevertheless, using a hypothetical ice-free scenario in the hydrological model, we indicate that ice-melt water constitutes an important water-supply component for Mapam Yumco and Paiku Co, in order to maintain a state close to equilibrium, whereas the water balance in the Nam Co and Tangra Yumco basins remains positive under ice-free conditions. These results highlight the benefits of linking hydrological modeling with atmospheric-model output and satellite-derived data, and the presented approach can be readily transferred to other data-scarce closed lake basins, opening new directions of research. Future work should go towards a better assessment of the model-chain uncertainties, especially in this region where observation data are scarce.

Abstract The generally negative effect of anthropogenic disturbance on the quality of habitats for species viability makes it a common focus of conservation assessment and prioritization efforts. Although many available spatial models and metrics (e.g., distance to or density of disturbance) characterize impact patterns of anthropogenic disturbance on the landscape, a general evaluation of model performance against empirical measurements of ecological integrity is lacking. We tested both distance‐based and disturbance‐density models in relation to ecological indicators. The models included roads, residential and commercial development, agricultural land use, mining, energy development infrastructure, and transmission structures as disturbance sources. Model parameters were based on expert input and results from the published literature. The disturbance models were tested against two disparate and independent measures of habitat quality: a floristic quality index and measures of greater sage‐grouse population integrity. Floristic quality scores were significantly lower in vegetation plots closer to disturbances in a general distance‐based disturbance model across Colorado. Although the proportion of variation in floristic quality explained by anthropogenic disturbance was relatively low (8.5–11.8%), it appeared to represent a ubiquitous baseline negative effect of proximity to anthropogenic disturbance on the quality of vegetation communities. For both distance‐ and density‐based greater sage‐grouse models, modeled disturbance indices were significantly lower (10–12 times) near active than historic leks, and numbers of males counted at leks increased significantly (3.2–3.4 times) as modeled disturbance decreased. Our findings indicate that as a general class, geospatial models can depict effects of anthropogenic disturbance on both plant communities and individual animal species. Empirical validation of disturbance models focused on other species or regions is recommended to further evaluate the utility and reliability of these methods.

The PK-4 laboratory consists of a direct current plasma tube into which microparticles are injected, forming a complex plasma. The microparticles acquire many electrons from the ambient plasma and are thus highly charged and interact with each other. If ion streams are present, wakes form downstream of the microparticles, which lead to an attractive term in the potential between the microparticles, triggering the appearance of microparticle strings and modifying the complex plasma into an electrorheological form. Here we report on a set of experiments on compressional waves in such a string fluid in the PK-4 laboratory during a parabolic flight and on board the International Space Station. We find a slowing of acoustic waves and hypothesize that the additional attractive interaction term leads to slower wave speeds than in complex plasmas with purely repulsive potentials. We test this hypothesis with simulations, and compare with theory.

We prove that the observable telegraph signal accompanying the bistability in the photon-blockade-breakdown regime of the driven and lossy Jaynes–Cummings model is the finite-size precursor of what in the thermodynamic limit is a genuine first-order phase transition. We construct a finite-size scaling of the system parameters to a well-defined thermodynamic limit, in which the system remains the same microscopic system, but the telegraph signal becomes macroscopic both in its timescale and intensity. The existence of such a finite-size scaling completes and justifies the classification of the photon-blockade-breakdown effect as a first-order dissipative quantum phase transition.

Elevated renal sympathetic nerve activity (RSNA) accompanies a variety of complex disorders, including obstructive sleep apnea, heart failure, and chronic kidney disease. Understanding pathophysiologic renal mechanisms is important for determining why hypertension is both a common sequelae and a predisposing factor of these disorders. The role of the brainstem in regulating RSNA remains incompletely understood. The pedunculopontine tegmentum (PPT) is known for regulating behaviors including alertness, locomotion, and rapid eye movement sleep. Activation of PPT neurons in anesthetized rats was previously found to increase splanchnic sympathetic nerve activity and blood pressure, in addition to altering breathing. The present study is the first investigation of the PPT and its potential role in regulating RSNA. Microinjections of DL-homocysteic acid (DLH) were used to probe the PPT in 100-μm increments in Nembutal-anesthetized rats to identify effective sites, defined as locations where changes in RSNA could be evoked. A total of 239 DLH microinjections were made in 18 rats, which identified 20 effective sites (each confirmed by the ability to evoke a repeatable sympathoexcitatory response). Peak increases in RSNA occurred within 10-20 seconds of PPT activation, with RSNA increasing by 104.5 ± 68.4% (mean ± standard deviation) from baseline. Mean arterial pressure remained significantly elevated for 30 seconds, increasing from 101.6 ± 18.6 mmHg to 135.9 ± 36.4 mmHg. DLH microinjections also increased respiratory rate and minute ventilation. The effective sites were found throughout the rostal-caudal extent of the PPT with most located in the dorsal regions of the nucleus. The majority of PPT locations tested with DLH microinjections did not alter RSNA (179 sites), suggesting that the neurons that confer renal sympathoexcitatory functions comprise a small component of the PPT. The study also underscores the importance of further investigation to determine whether sympathoexcitatory PPT neurons contribute to adverse renal and cardiovascular consequences of diseases such as obstructive sleep apnea and heart failure.

One of the major challenges for water balance studies in the remote and mostly ungauged region of the Tibetan Plateau is the lack of suitable and reliable climate data to drive hydrological models. Ground observations are rare in the high-mountainous region of the Nam Co basin and only global and regional gridded climate products are available as model input data, but these data sets need to be carefully analysed if used as driving force for hydrological modelling. In this study, various global and regional gridded data products for temperature and precipitation were compared to assess spatio-temporal deviations between several data sets. For the comparison absolute and relative differences of annual and seasonal long-term means were calculated. Climatic trends were analysed by using the non-parametric Mann-Kendall trend test. In addition, gridded climate data sets were compared to meteorological observations in order to evaluate their plausibility. The comparative statistical analysis showed significant differences in the magnitude, the seasonality, the spatial pattern and the trend behaviour of the analysed climate variables, in particular for precipitation data. The identified inconsistencies underpin the necessity to quantify the uncertainty of such climate data. Moreover, the presented study highlights the importance of further research efforts to develop regional climate data sets with finer resolutions to reduce the model's uncertainty resulting from climate input data. Such higher resolution is needed for a sufficient representation of regional topographic and orographic effects in order to simulate important hydrological processes in mountainous areas like snow accumulation and melting.

In this paper, a method is presented to estimate excess nitrogen on large scales considering single field processes. The approach was implemented by using the physically based model J2000-S to simulate the nitrogen balance as well as the hydrological dynamics within meso-scale test catchments. The model input data, the parameterization, the results and a detailed system understanding were used to generate the regression tree models with GUIDE (Loh, 2002). For each landscape type in the federal state of Thuringia a regression tree was calibrated and validated using the model data and results of excess nitrogen from the test catchments. Hydrological parameters such as precipitation and evapotranspiration were also used to predict excess nitrogen by the regression tree model. Hence they had to be calculated and regionalized as well for the state of Thuringia. Here the model J2000g was used to simulate the water balance on the macro scale. With the regression trees the excess nitrogen was regionalized for each landscape type of Thuringia. The approach allows calculating the potential nitrogen input into the streams of the drainage area. The results show that the applied methodology was able to transfer the detailed model results of the meso-scale catchments to the entire state of Thuringia by low computing time without losing the detailed knowledge from the nitrogen transport modeling. This was validated with modeling results from Fink (2004) in a catchment lying in the regionalization area. The regionalized and modeled excess nitrogen correspond with 94%. The study was conducted within the framework of a project in collaboration with the Thuringian Environmental Ministry, whose overall aim was to assess the effect of agro-environmental measures regarding load reduction in the water bodies of Thuringia to fulfill the requirements of the European Water Framework Directive (Bäse et al., 2007; Fink, 2006; Fink et al., 2007).

The scientific sound definition of measures to achieve the goals of the EU water framework directive (WFD) acquires spatially distributed analyses of the water and substance dynamics in meso- to macro-scale catchments. For this purpose, modelling tools or systems are needed which are robust and fast enough to be applied on such scales, but which are also able to simulate the impact of changes on single fields or small areas of a specific land use in the catchment. To face these challenges, we combined the fully-distributed hydrological model J2000 with the nitrogen transport routines of the Soil Water Assessment Tool SWAT model, which are normally applied in a semi-distributive approach. With this combination, we could extend the quantitative focus of J2000 with qualitative processes and could overcome the semi-distributed limitation of SWAT. For the implementation and combination of the components, we used the Jena Adaptable Modelling System JAMS (Kralisch and Krause, 2006) which helped tremendously in the relatively rapid and easy development of the new resultant model J2000-S (J2000-Substance). The modelling system was applied in the upper Gera watershed, located in Thuringia, Germany. The catchment has an area of 844 km2 and includes three of the typical landscape forms of Thuringia. The application showed, that the new modelling system was able to reproduce the daily hydrological as well as the nitrogen dynamics with a sufficient quality. The paper will describe the results of the new model and compare them with the results obtained with the original semi-distributed application of SWAT.

The application of the hydrological process-oriented model J2000 (J2K) is part of a cooperation project between the Thuringian Environmental Agency (Thüringer Landesanstalt für Umwelt und Geologie – TLUG) and the Department of Geoinformatics of the Friedrich-Schiller-University Jena focussing on the implementation of the EU water framework directive (WFD). In the first project phase J2K was parametrised and calibrated for a mesoscale catchment to quantify if it can be used as hydrological part of a multi-objective tool-box needed for the implementation of the WFD. The main objectives for that pilot study were: The development and application of a suitable distribution concept which provide the spatial data basis for various tasks and which reflects the specific physiogeographical variability and heterogeneity of river basins adequately. This distribution concept should consider the following constraints: The absolute number of spatial entities, which forms the basis for any distributive modelling should be as small as possible, but the spatial distributed factors, which controls quantitative and qualitative hydrological processes should not be generalised to much. The distribution concept of hydrological response units HRUs (Flügel, 1995) was selected and enhanced by a topological routing scheme (Staudenrausch, 2001) for the simulation of lateral flow processes. J2K should be calibrated for one subbasin of the pilot watershed only. Then the parameter set should be used on the other subbasins (referred as transfer basins) to investigate and quantify the transferability of a calibrated model and potential spatial dependencies of its parameter set. In addition, potential structural problems in the process description should be identified by the transfer to basins which show a different process dominance as the one which was used for calibration does. Model calibration and selection of efficiency criteria for the quantification of the model quality should be based on a comprehensive sensitivity and uncertainty analysis (Bäse, 2005) and multi-response validations with independent data sets (Krause and Flügel, 2005) carried out in advance in the headwater part of the calibration basin. To obtain good results in the transfer basins the calibrated parameter set could be adjusted slightly. This step was considered as necessary because of specific constraints which were not of significant importance in the calibration basin. This readjustment should be carried out on parameters which show a sensitive reaction on the identified differences in the environmental setup. Potential scaling problems of the process description, distribution concept or model structure should be identified by the comparison of the modelling results obtained in a small headwater region of the calibration basin with observed streamflow to find out if the selected efficiency measures show a significant change.

The cellular and physiologic mechanisms that regulate the resolution of inflammation remain poorly defined despite their widespread importance in improving inflammatory disease outcomes. We studied the resolution of two cardinal signs of inflammation-pain and swelling-by investigating molecular mechanisms that regulate neural and lymphatic vessel remodeling during the resolution of corneal inflammation. A mouse model of corneal inflammation and wound recovery was developed to study this process in vivo. Administration of nerve growth factor (NGF) increased pain sensation and inhibited neural remodeling and lymphatic vessel regression processes during wound recovery. A complementary in vivo approach, the corneal micropocket assay, revealed that NGF-laden pellets stimulated lymphangiogenesis and increased protein levels of VEGF-C. Adult human dermal lymphatic endothelial cells did not express canonical NGF receptors TrkA and p75NTR or activate downstream MAPK- or Akt-pathway effectors in the presence of NGF, although NGF treatment increased their migratory and tubulogenesis capacities in vitro. Blockade of the VEGF-R2/R3 signaling pathway ablated NGF-mediated lymphangiogenesis in vivo. These findings suggest a hierarchical relationship with NGF functioning upstream of the VEGF family members, particularly VEGF-C, to stimulate lymphangiogenesis. Taken together, these studies show that NGF stimulates lymphangiogenesis and that NGF may act as a pathogenic factor that negatively regulates the normal neural and lymphatic vascular remodeling events that accompany wound recovery.

Nonequilibrium phase transitions exist in damped-driven open quantum systems when the continuous tuning of an external parameter leads to a transition between two robust steady states. In second-order transitions this change is abrupt at a critical point, whereas in first-order transitions the two phases can coexist in a critical hysteresis domain. Here, we report the observation of a first-order dissipative quantum phase transition in a driven circuit quantum electrodynamics system. It takes place when the photon blockade of the driven cavity-atom system is broken by increasing the drive power. The observed experimental signature is a bimodal phase space distribution with varying weights controlled by the drive strength. Our measurements show an improved stabilization of the classical attractors up to the millisecond range when the size of the quantum system is increased from one to three artificial atoms. The formation of such robust pointer states could be used for new quantum measurement schemes or to investigate multiphoton phases of finite-size, nonlinear, open quantum systems.

Midkine (MDK) is a heparin-binding growth factor that is highly expressed in many malignant tumors, including lung cancers. MDK activates the PI3K pathway and induces anti-apoptotic activity, in turn enhancing the survival of tumors. Therefore, the inhibition of MDK is considered a potential strategy for cancer therapy. In the present study, we demonstrate a novel small molecule compound (iMDK) that targets MDK. iMDK inhibited the cell growth of MDK-positive H441 lung adenocarcinoma cells that harbor an oncogenic KRAS mutation and H520 squamous cell lung cancer cells, both of which are types of untreatable lung cancer. However, iMDK did not reduce the cell viability of MDK-negative A549 lung adenocarcinoma cells or normal human lung fibroblast (NHLF) cells indicating its specificity. iMDK suppressed the endogenous expression of MDK but not that of other growth factors such as PTN or VEGF. iMDK suppressed the growth of H441 cells by inhibiting the PI3K pathway and inducing apoptosis. Systemic administration of iMDK significantly inhibited tumor growth in a xenograft mouse model in vivo. Inhibition of MDK with iMDK provides a potential therapeutic approach for the treatment of lung cancers that are driven by MDK.