One major challenge in synthetic biology is the deleterious impacts of cellular stress caused by expression of heterologous pathways, sensors, and circuits. Feedback control and dynamic regulation ...are broadly proposed strategies to mitigate this cellular stress by optimizing gene expression levels temporally and in response to biological cues. While a variety of approaches for feedback implementation exist, they are often complex and cannot be easily manipulated. Here, we report a strategy that uses RNA transcriptional regulators to integrate additional layers of control over the output of natural and engineered feedback responsive circuits. Called riboregulated switchable feedback promoters (rSFPs), these gene expression cassettes can be modularly activated using multiple mechanisms, from manual induction to autonomous quorum sensing, allowing control over the timing, magnitude, and autonomy of expression. We develop rSFPs in
to regulate multiple feedback networks and apply them to control the output of two metabolic pathways. We envision that rSFPs will become a valuable tool for flexible and dynamic control of gene expression in metabolic engineering, biological therapeutic production, and many other applications.
Varroa destructor
is a major threat for apiculture worldwide. A successful approach to control this parasite must include the application of effective treatments at the correct time. To understand ...the effect that treatment timing has on
Varroa
populations at different seasons, we conducted an experiment using a dataset comprising two separate field trials over multiple years, both trials containing four apiary sites composed of 20 honey bee colonies across an area representative of north central Florida environments. Before the start of the season, colonies were treated with two acaricides simultaneously to bring the
Varroa
populations to ∼0.25 mites/100 bees. Following treatment, we monitored the mite populations monthly via alcohol washes. Our results show that the temporal efficacy of
Varroa
treatments varies across seasons. We observed that it takes about 4–5 months after treatment in winter and spring for mite populations to return to the standard economical threshold (3 mites/100 bees). Nevertheless, there is a steeper increase in mite populations (<3 months to exceed the economic threshold) after treating colonies in summer and fall. The level of infestation that leads to colony collapse and the rate of colony decline also varied by season. To our knowledge, this is the first study evaluating seasonal effects on
Varroa
population growth and the first model of
Varroa
population growth in Florida, USA. Our results serve as a foundation for
Varroa
treatment models, aiding beekeepers in the future as a part of a holistic approach to control this devastating honey bee parasite.
Eight platinum(II) complexes with anticancer potential have been synthesised and characterised. These complexes are of the type Pt(I(L))(A(L))(2+), where I(L) is either ...dipyrido3,2-f:2',3'-hquinoxaline (dpq) or 2,3-dimethyl-dpq (23Me2dpq) and A(L) is one of the R,R or S,S isomers of either 1,2-diaminocyclohexane (SS-dach or RR-dach) or 1,2-diaminocyclopentane (SS-dacp or RR-dacp). The CT-DNA binding of these complexes and a series of other complexes were assessed using fluorescent intercalator displacement assays, resulting in unexpected trends in DNA binding affinity. The cytotoxicity of the eight synthesised compounds was determined in the L1210 cell line; the most cytotoxic of these were Pt(dpq)(SS-dach)Cl2 and Pt(dpq)(RR-dach)Cl2, with IC50 values of 0.19 and 0.80 μM, respectively. The X-ray crystal structure of the complex Pt(dpq)(SS-dach)(ClO4)2·1.75H2O is also reported.
Most evidence about dementia risk comes from relatively affluent people of White European ancestry. We aimed to determine the association between ethnicity, area level socioeconomic deprivation and ...dementia risk, and the extent to which variation in risk might be attributable to known modifiable clinical risk factors and health behaviours.
In this nested case-control study, we analysed data from primary care medical records of a population of 1,016,277 from four inner East London boroughs, United Kingdom, collected between 2009 and 2018. The outcome measures were odds ratios for dementia according to ethnicity and deprivation, before and after the addition of major modifiable risk factors for dementia; and weighted population attributable risk for comparison between individual risk factors.
We identified 4137 dementia cases and 15,754 matched controls (mean age for cases and controls were 80·7 years, (SD 8·7); 81·3 years, (SD 8·9) respectively, range 27–103). Black and South Asian ethnicity were both associated with increased risk of dementia relative to White (odds ratios 95% CI: Black 1·43 1·31–1·56; South Asian 1.17 1·06–1·29). Area-level deprivation was independently associated with an increased risk of dementia in a dose-dependent manner. Black and South Asian ethnicity were both associated with a younger age at dementia diagnosis (odds ratios 95%CI: 0·70 0·61–0·80 and 0·55 0·47–0·65, respectively). Population attributable risk was higher for ethnicity (9·7%) and deprivation (11·7%) than for any established modifiable risk factor in this population.
Ethnicity and area-level deprivation are independently associated with dementia risk in East London. This effect may not be attributable to the effect of known risk factors.
Barts Charity (MGU0366).
In pancreatic ductal adenocarcinoma (PDAC), differentiation of pancreatic stellate cells (PSCs) into myofibroblast-like cancer-associated fibroblasts (CAFs) can both promote and suppress tumor ...progression. Here, we show that the Rho effector protein kinase N2 (PKN2) is critical for PSC myofibroblast differentiation. Loss of PKN2 is associated with reduced PSC proliferation, contractility, and alpha-smooth muscle actin (α-SMA) stress fibers. In spheroid co-cultures with PDAC cells, loss of PKN2 prevents PSC invasion but, counter-intuitively, promotes invasive cancer cell outgrowth. PKN2 deletion induces a myofibroblast to inflammatory CAF switch in the PSC matrisome signature both in vitro and in vivo. Further, deletion of PKN2 in the pancreatic stroma induces more locally invasive, orthotopic pancreatic tumors. Finally, we demonstrate that a PKN2KO matrisome signature predicts poor outcome in pancreatic and other solid human cancers. Our data indicate that suppressing PSC myofibroblast function can limit important stromal tumor-suppressive mechanisms, while promoting a switch to a cancer-supporting CAF phenotype.
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•The Rho effector kinase PKN2 is a key regulator of myofibroblast phenotypes•PKN2KO induces a myofibroblast to inflammatory CAF switch in mouse pancreatic tumors•Stromal deletion of PKN2 promotes more locally invasive orthotopic pancreatic tumors•A PKN2KO matrisome signature predicts poor outcome in human pancreatic cancer
Murray and Menezes et al. show that the Rho effector kinase PKN2 is essential for maintaining the myofibroblast phenotype of pancreatic stellate cells. Deletion of stromal PKN2 induces a switch to an inflammatory CAF phenotype both in vitro and in vivo, and this is associated with more invasive pancreatic tumors.
The degree of physiological responses to individual antipsychotic drugs is unclear in children and adolescents. With network meta-analysis, we aimed to investigate the effects of various ...antipsychotic medications on physiological variables in children and adolescents with neuropsychiatric and neurodevelopmental conditions.
For this network meta-analysis, we searched Medline, EMBASE, PsycINFO, Web of Science, and Scopus from database inception until Dec 22, 2023, and included randomised controlled trials comparing antipsychotics with placebo in children or adolescents younger than 18 years with any neuropsychiatric and neurodevelopmental condition. Primary outcomes were mean change from baseline to end of acute treatment in bodyweight, BMI, fasting glucose, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, prolactin, heart rate, systolic blood pressure (SBP), and QT interval corrected for heart rate (QTc) for patients receiving either active treatment or placebo. For multigroup trials reporting several doses, we calculated a summary value for each physiological variable for all doses. After transitivity assessment, we fitted frequentist random-effects network meta-analyses for all comparisons in the network. A Kilim plot was used to summarise the results for all treatments and outcomes, providing information regarding the strength of the statistical evidence of treatment effects, using p values. Network heterogeneity was assessed with τ, risk of bias of individual trials was assessed with the Cochrane Collaboration's Tool for Assessing Risk of Bias, and the credibility of findings from each network meta-analysis was assessed with the Confidence in Network Meta-Analysis (CINEMA) app. This study is registered on PROSPERO (CRD42021274393).
Of 6676 studies screened, 47 randomised controlled trials were included, which included 6500 children (mean age 13·29 years, SD 2·14) who received treatment for a median of 7 weeks (IQR 6–8) with either placebo (n=2134) or one of aripiprazole, asenapine, blonanserin, clozapine, haloperidol, lurasidone, molindone, olanzapine, paliperidone, pimozide, quetiapine, risperidone, or ziprasidone (n=4366). Mean differences for bodyweight change gain compared with placebo ranged from –2·00 kg (95% CI –3·61 to –0·39) with molindone to 5·60 kg (0·27 to 10·94) with haloperidol; BMI –0·70 kg/m2 (–1·21 to –0·19) with molindone to 2·03 kg/m2 (0·51 to 3·55) with quetiapine; total cholesterol –0·04 mmol/L (–0·39 to 0·31) with blonanserin to 0·35 mmol/L (0·17 to 0·53) with quetiapine; LDL cholesterol –0·12 mmol/L (–0·31 to 0·07) with risperidone or paliperidone to 0·17 mmol/L (–0·06 to 0·40) with olanzapine; HDL cholesterol 0·05 mmol/L (–0·19 to 0·30) with quetiapine to 0·48 mmol/L (0·18 to 0·78) with risperidone or paliperidone; triglycerides –0·03 mmol/L (–0·12 to 0·06) with lurasidone to 0·29 mmol/L (0·14 to 0·44) with olanzapine; fasting glucose from –0·09 mmol/L (–1·45 to 1·28) with blonanserin to 0·74 mmol/L (0·04 to 1·43) with quetiapine; prolactin from –2·83 ng/mL (–8·42 to 2·75) with aripiprazole to 26·40 ng/mL (21·13 to 31·67) with risperidone or paliperidone; heart rate from –0·20 bpm (–8·11 to 7·71) with ziprasidone to 12·42 bpm (3·83 to 21·01) with quetiapine; SBP from –3·40 mm Hg (–6·25 to –0·55) with ziprasidone to 10·04 mm Hg (5·56 to 14·51) with quetiapine; QTc from –0·61 ms (–1·47 to 0·26) with pimozide to 0·30 ms (–0·05 to 0·65) with ziprasidone.
Children and adolescents show varied but clinically significant physiological responses to individual antipsychotic drugs. Treatment guidelines for children and adolescents with a range of neuropsychiatric and neurodevelopmental conditions should be updated to reflect each antipsychotic drug's distinct profile for associated metabolic changes, alterations in prolactin, and haemodynamic alterations.
UK Academy of Medical Sciences, Brain and Behaviour Research Foundation, UK National Institute of Health Research, Maudsley Charity, the Wellcome Trust, Medical Research Council, National Institute of Health and Care Research Biomedical Centre at King's College London and South London and Maudsley NHS Foundation Trust, the Italian Ministry of University and Research, the Italian National Recovery and Resilience Plan, and Swiss National Science Foundation.
Dynamically porous metal-organic frameworks (MOFs) with a chiral quartz-based structure have been synthesized from the multidentate ligand 2,2'-dihydroxybiphenyl-4,4'-dicarboxylate (H2diol). ...Compounds Ni(II)(H2diol)(S)2·xS (where S = DMF or DEF) show marked changes in 77 K N2 uptake between partially desolvated Ni(II)(H2diol)(S)2 (only the pore solvent is removed) and fully desolvated Ni(II)(H2diol) forms. Furthermore, Ni(II)(H2diol)(DMF)2 displays additional solvent-dependent porosity through the rotation of DMF molecules attached to the axial coordination sites of the Ni(II) centre. A unique feature of the four coordinate Ni(II) centre in Ni(II)(H2diol) is the dynamic response to its chemical environment. Exposure of Ni(II)(H2diol) to H2O and MeOH vapour leads to coordination of both axial sites of the Ni centres and to the generation of a solvated framework, whereas exposure to EtOH, DMF, acetone, and MeCN does not lead to any change in metal coordination or structure metrics. MeOH vapour adsorption was able to be tracked by time-dependent magnetometry as the solvated and desolvated structures have different magnetic moments. Solvated and desolvated forms of the MOF show remarkable differences in their thermal expansivities; Ni(II)(H2diol)(DMF)2·DMF displays marked positive thermal expansion (PTE) in the c-axis, yet near to zero thermal expansion, between 90 and 450 K, is observed for Ni(II)(H2diol). These new MOF architectures demonstrate a dynamic structural and colourimetric response to selected adsorbates via a unique mechanism that involves a reversible change in the coordination environment of the metal centre. These coordination changes are mediated throughout the MOF by rotational mobility about the biaryl bond of the ligand.
The genus
includes several agricultural pests globally.
was reported in several countries in South America in 2013, and in Puerto Rico, in 2014. This territory is considered an agricultural hub, with ...a high-input system of seed production in the southern region of the island, and also at the edge of the continental U.S. Possible natural dispersion of populations of
from the Caribbean or other Central American regions poses a continuing risk to the U.S. This study was performed during the post-detection scenario of
in Puerto Rico, from 2018 to 2021. A year-round pheromone trapping program of adult males indicated an increase in the population from October to March and differences in the occurrence of
spp. between the municipalities Juan Diaz and Salinas. The proportion of
/
and detection of congeneric hybrids between these species were assessed based on genital morphology and DNA analysis. Interestingly, neither
nor expected hybrids were detected in the present study. The susceptibility of
populations to the insecticides Spinetoram, Emamectin benzoate, Chlorantraniliprole, and Esfenvalerate was assessed, and an overall significant effect of insecticide susceptibility was detected. Chlorantraniliprole and Emamectin benzoate had the highest efficacy. These results contribute to the Integrated Pest Management and Insect resistance management programs to
spp. in Puerto Rico. In addition, provide validated information to be considered in mitigation plans, in the scenario of an invasion of
in the continental U.S.
Investigating glacier mass balance via the use of numerical models provides an important insight into glacier‐climate interactions and allows for the assessment of future changes in sea level and ...local water resources. The application of mass balance models to unmonitored regions has previously been inhibited by the inadequate spatial coverage of local meteorological observations. One way to overcome this problem is through the use of climate reanalysis products. In this paper we evaluate the ability of the European Centre for Medium‐Range Forecasts ERA‐40 reanalysis to drive a surface mass balance model of Midre Lovénbreen, northwest Spitsbergen, Svalbard. The ERA‐40 reanalysis is validated and bias‐corrected against long‐term observations from two nearby in situ weather stations. The model is calibrated over the period of mass balance observations (1968–2001) using a downhill simplex parameter optimization technique to minimize the error between observed and simulated mass balances. The calibrated model is then used to extend the mass balance record of Midre Lovénbreen back to the beginning of the reanalysis in 1958. Overall, the ERA‐40 reanalysis is found to correspond sufficiently well with surface observations to be used for mass balance modeling. When driven using the ERA‐40 reanalysis, the calibrated surface mass balance model performs very well. The area‐averaged cumulative errors for winter, summer, and net balances are all very small over the period 1968–2001 (<0.3 m water equivalent (w.e.)). For the centerline stakes the correlation coefficients between observed and modeled net, winter, and summer balances are 0.83, 0.84, and 0.77, respectively. Using the hindcasted mass balances, a mean cumulative mass loss of −17.8 ± 3.7 m w.e. is estimated over the 44 year period 1958–2001.
Physically based models are valuable tools for exploring the detailed spatial and temporal responses of glaciers and ice sheets to climate forcing. However, while the last two decades have seen ...considerable progress in the development of increasingly sophisticated numerical descriptions, very little attention has been given to simulation uncertainty. In particular, glaciological models have traditionally been calibrated (or “tuned”) in order to identify a single set of parameters (e.g., snow density, surface albedo, temperature lapse rate) such that the model's behavior closely matches real‐world observations. The present study disputes this classical approach by demonstrating that it is often difficult (if not impossible) to find a single “best” solution. Instead, multiple equally plausible parameter sets will usually exist. To address this limitation, we present a novel application of a calibration technique previously not used in glacial modeling – multiobjective optimization – designed to identify multiple optimal parameter sets that fit different characteristics of available observations, thereby enabling an assessment of the uncertainty associated with predictions. The strength and applicability of our approach is illustrated through the implementation of a surface mass balance model for two glaciers in Svalbard: Midre Lovénbreen and Kongsvegen. The model is forced using the ERA‐40 reanalysis and calibrated against available mass balance measurements. The overall uncertainty range in modeled cumulative annual surface mass balance is −7.84 to −14.02 m w.e. for Midre Lovénbreen (over the period 1968–2001) and −0.91 to +9.80 m w.e. for Kongsvegen (over the period 1987–2001). The calibrated model is used to extend the mass balance records of the two glaciers back to the beginning of the ERA‐40 reanalysis, giving a cumulative loss of loss of 13.2 ± 3.3 m w.e. for Midre Lovénbreen and a cumulative gain of 5.3 ± 3.4 m w.e. for Kongsvegen over the period 1958–2001. The multiobjective optimization results also indicate that current mass balance models may contain structural inadequacies relating to how the mass balance gradient is simulated.
Key Points
To highlight the inherent uncertainty associated with glaciological modeling
To introduce the concept of multiobjective optimization
To highlight the need for robust uncertainty estimation
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