Search

Abstract The heterotrimeric G‐protein complex is minimally composed of Gα, Gβ, and Gγ subunits. In the classic scenario, the G‐protein complex is the nexus in signaling from the plasma membrane, where the heterotrimeric G‐protein associates with heptahelical G‐protein‐coupled receptors (GPCRs), to cytoplasmic target proteins called effectors. Although a number of effectors are known in metazoans and fungi, none of these are predicted to exist in their canonical forms in plants. To identify ab initio plant G‐protein effectors and scaffold proteins, we screened a set of proteins from the G‐protein complex using two‐hybrid complementation in yeast. After deep and exhaustive interrogation, we detected 544 interactions between 434 proteins, of which 68 highly interconnected proteins form the core G‐protein interactome. Within this core, over half of the interactions comprising two‐thirds of the nodes were retested and validated as genuine in planta. Co‐expression analysis in combination with phenotyping of loss‐of‐function mutations in a set of core interactome genes revealed a novel role for G‐proteins in regulating cell wall modification.

We provide an overview of experiments exploring resonances in the collision of ultracold clouds of atoms. Using a laser-based accelerator that capitalises on the energy resolution provided by the ultracold atomic setting, we unveil resonance phenomena such as Feshbach and shape resonances in their quintessential form by literally photographing the halo of outgoing scattered atoms. We exploit the tunability of magnetic Feshbach resonances to instigate an interplay between scattering resonances. By experimentally recording the scattering in a parameter space spanned by collision energy and magnetic field, we capture the imprint of the S-matrix pole flow in the complex energy plane. After revisiting experiments that place a Feshbach resonance in the proximity of a shape resonance and an anti-bound state, respectively, we discuss the possibility of using S-matrix pole interplay between two Feshbach resonances to create a bound-state-in-the-continuum. [ABSTRACT FROM AUTHOR]

Background: Children with severe atopic dermatitis (AD) have a multidimensional disease burden. Objective: Here we assess the clinically meaningful improvements in AD signs, symptoms, and quality of life (QoL) in children aged 6–11 years with severe AD treated with dupilumab compared with placebo. Methods: R668-AD-1652 LIBERTY AD PEDS was a randomized, double-blinded, placebo-controlled, parallel-group, phase III clinical trial of dupilumab with concomitant topical corticosteroids (TCS) in children aged 6–11 years with severe AD. This post hoc analysis focuses on 304 patients receiving either dupilumab or placebo with TCS and assessed the percentage of patients considered responsive to dupilumab treatment at week 16. Results: At week 16, almost all patients receiving dupilumab + TCS (95%) demonstrated clinically meaningful improvements in AD signs, symptoms, or QoL compared with placebo + TCS (61%, p < 0.0001). Significant improvements were seen as early as week 2 and sustained through the end of the study in the full analysis set (FAS) and the subgroup of patients with an Investigator's Global Assessment score greater than 1 at week 16. Limitations: Limitations include the post hoc nature of the analysis and that some outcomes were not prespecified; the small number of patients in some subgroups potentially limits generalizability of findings. Conclusion: Treatment with dupilumab provides significant and sustained improvements within 2 weeks in AD signs, symptoms, and QoL in almost all children with severe AD, including those who did not achieve clear or almost clear skin by week 16. Trial Registration: NCT03345914. E91VSsKmsTg9JpbJbaReFk Video Abstract: Does dupilumab provide clinically meaningful responses in children 6 to 11 years old with severe atopic dermatitis? (MP4 99484 kb) [ABSTRACT FROM AUTHOR]

Background: Adults aged ≥ 60 years are often underrepresented in atopic dermatitis (AD) clinical trials; age-related comorbidities may impact treatment efficacy and safety. Objective: The aim was to report dupilumab efficacy and safety in patients aged ≥ 60 years with moderate-to-severe AD. Methods: Data were pooled from four randomized, placebo-controlled dupilumab trials of patients with moderate-to-severe AD (LIBERTY AD SOLO 1 and 2, LIBERTY AD CAFÉ, and LIBERTY AD CHRONOS) and stratified by age (< 60 [N = 2261] and ≥ 60 [N = 183] years). Patients received dupilumab 300 mg every week (qw) or every 2 weeks (q2w), or placebo with/without topical corticosteroids. Post hoc efficacy at week 16 was examined using broad categorical and continuous assessments of skin lesions, symptoms, biomarkers, and quality of life. Safety was also assessed. Results: In the ≥ 60-year-old group at week 16, a greater proportion of dupilumab-treated patients achieved an Investigator's Global Assessment score of 0/1 (q2w: 44.4%; qw: 39.7%) and 75% improvement in Eczema Area and Severity Index (63.0%; 61.6%) versus placebo (7.1% and 14.3%, respectively; P < 0.0001). Type 2 inflammation biomarkers (immunoglobulin E and thymus and activation-regulated chemokine) were also significantly reduced in dupilumab- versus placebo-treated patients (P < 0.01). Results were similar in the < 60-year-old group. The exposure-adjusted incidences of adverse events in dupilumab-treated patients were generally similar to those receiving placebo, with numerically fewer treatment-emergent adverse events in the dupilumab-treated ≥ 60-year-old group versus placebo. Limitations: There were fewer patients in the ≥ 60-year-old group; post hoc analyses. Conclusion: Dupilumab improved AD signs and symptoms in patients aged ≥ 60 years; results were comparable to those in patients aged < 60 years. Safety was consistent with the known dupilumab safety profile. Trial Registration: ClinicalTrials.gov: NCT02277743, NCT02277769, NCT02755649, NCT02260986. DAhitXvUt5z-PjCq13QV7Z Does dupilumab benefit adults aged 60 years and older with moderate-to-severe atopic dermatitis?(MP4 20,787 KB) [ABSTRACT FROM AUTHOR]

Given the differences in geomorphology, climate, hydrology, and human activities in various regions, lake chemometrics may also vary. However, the spatial distribution of lake chemistry and the factors affecting such pattern are still unclear. Here, we collected data for carbon, nitrogen, and phosphorus from published literature and databases in 224 lakes and calculated the trophic status index to represent the nutrient classification state of lakes. We found that lakes with high carbon concentrations were located in the Tibet-Qinghai Limnetic Region of western China, whereas lakes with high nitrogen and phosphorus concentrations were located in the Inner Mongolia-Xinjiang Limnetic Region and Northeast Limnetic Region of northern China. Areas with larger cropland and urban residential land (such as the junction of the three lake regions, i.e., the Northeast Limnetic Region, East Limnetic Region, and Inner Mongolia-Xinjiang Limnetic Region) tended to have lakes with high nitrogen and phosphorus concentrations. Our analysis suggested that spatial distribution of carbon, nitrogen, and phosphorus concentrations reflect the effect of climate, geomorphology, and land use in each lake region and nationwide. [ABSTRACT FROM AUTHOR]

Purpose: Grasslands are the most extensive vegetation type in the terrestrial ecosystem and have an important role in the soil phosphorus (P) cycle. Many nutrient addition and warming experiments have been conducted in grasslands; however, the global pattern of nutrient addition and experimental warming impacts on soil P cycle is unclear. Methods: We conducted a meta-analysis of 68 publications to synthesize the mechanisms underlying global grassland ecosystem responses to nutrient addition and experimental warming. Results: Our analysis indicated that nitrogen (N) addition reduced microbial biomass P (− 11.2%) but increased litter P concentration (+ 15.5%) and available P (+ 14.2%). Experimental warming reduced microbial biomass P (− 10.5%) and available P (− 6.7%) but increased litter P concentration (+ 46.2%). P addition increased available P (+ 222.3%) and microbial biomass P (+ 98.1%). The available P response to nutrient addition and experimental warming was more sensitive in temperate grasslands than in alpine grasslands. The responses of soil total and available P to nutrient addition depended on environmental conditions such as air temperature and soil pH. Conclusion: Our results suggest that N addition may promote P mineralization and possibly stimulate the transformation of refractory or resistant forms of soil inorganic P, whereas experimental warming accelerates the P cycle by regulating plant acquisition and enzyme activity. Environmental factors (e.g., temperature, precipitation, pH) affect the soil P response to nutrient addition by altering microbial and enzymatic activities. It is crucial to understand the dynamic changes in soil microbial and enzyme activities to predict the P cycle in grassland soils in the future. [ABSTRACT FROM AUTHOR]

Background: Data regarding long-term outcomes following percutaneous cholecystostomy (PC) are limited, and comparisons to cholecystectomy (CCY) are lacking. We hypothesized that chronic disease burden would predict 1-year mortality following PC, and that outcomes following PC and CCY would be similar when controlling for preprocedural risk factors.Methods: We performed a 10-year retrospective cohort analysis of patients with acute cholecystitis managed by PC (n = 114) or CCY (n = 234). Treatment response was assessed by systemic inflammatory response syndrome (SIRS) criteria at PC/CCY and 72 h later. Logistic regression identified predictors of 30-day and 1-year mortality following PC. PC and CCY patients were matched by age, Tokyo Guidelines (TG13) cholecystitis severity grade, and VASQIP calculator predicted mortality (n = 42/group).Results: The presence of SIRS at 72 h following PC was associated with 30-day mortality [OR 8.9 (95% CI 2.6-30)]. SIRS at 72 h was present in and 21.4% of all PC patients, significantly higher than unmatched CCY patients (4.7%, p = 0.048). Independent predictors of 1-year mortality following PC were DNR status [19.7 (2.1-186)], disseminated cancer [7.5 (2.1-26)], and congestive heart failure [3.9 (1.4-11)]. PC patients with none of these risk factors had 17.9% 90-day mortality and no deaths after 90 days; late deaths continued to occur among patients with DNR, CHF, or disseminated cancer. At baseline, PC patients had greater acute and chronic disease burden than CCY patients. After matching, PC and CCY patients had similar age (69 vs. 70 years), TG13 grade (2.4 vs. 2.4), and predicted 30-day mortality (5.5 vs. 6.8%). Matched PC patients had higher 30-day mortality (14.3 vs. 2.4%, p = 0.109) and 180-day mortality (28.6 vs. 7.1%, p = 0.048).Conclusions: Treatment response to PC predicted 30-day mortality; DNR status, and chronic diseases predicted 1-year mortality. Although the matching procedure did not eliminate selection bias, PC was associated with persistent systemic inflammation and higher long-term mortality than CCY. [ABSTRACT FROM AUTHOR]

Introduction: Patients with sporadic breast cancer (BC) have low contralateral breast cancer risk (CLBCR; approximately 0.7% per annum) and contralateral prophylactic mastectomy (CPM) offers no survival advantage. CPM with autologous reconstruction (AR) has major morbidity and resource implications.Objective: The aim of this study was to review the impact of PREDICT survival estimates and lifetime CLBCR scores on decision making for CPM in patients with unilateral BC.Methods: Of n = 272 consecutive patients undergoing mastectomy and AR, 252 were included. Five- and 10-year survival was computed with the PREDICT(V2) online prognostication tool, using age and clinicopathological factors. Based on family history (FH) and tumor biology, CLBCR was calculated using validated BODICEA web-based software. Survival scores were correlated against CLBCR estimates to identify patients receiving CPM with ‘low’ CLBCR (< 30% lifetime risk) and poor prognosis (5-year survival < 80%). Patients with ‘high’ CLBCR receiving unilateral mastectomy (UM) were similarly identified (UK National Institute of Health and Care Excellence [NICE] criteria for CPM, ≥ 30% lifetime BC risk). Justifications motivating CPM were investigated.Results: Of 252 patients, 215 had UM and 37 had bilateral mastectomy and AR. Only 23 (62%) patients receiving CPM fulfilled the NICE criteria. Of 215 patients, 5 (2.3%) failed to undergo CPM despite high CLBCR and good prognosis. CPMs were performed, at the patient’s request, for no clear justification (n = 8), contralateral non-invasive disease, and/or FH (n = 5), FH alone (n = 4) and ipsilateral cancer recurrence-related anxiety (n = 3).Conclusion: In the absence of prospective risk estimates of CLBCR and prognosis, certain patients receive CPM and reconstruction despite modest CLBCR, yet a proportion of patients with good prognoses and substantial risk are not undergoing CPM. [ABSTRACT FROM AUTHOR]

A correction is presented to the article " Efcacy and Safety of Dupilumab Maintained in Adults ≥ 60 Years of Age with Moderate‑to‑Severe A topic Dermatitis: Analysis of Pooled Data from Four Randomized Clinical Trials" which appeared in the February 20, 2023 issue.

Ultracold atomic gases have realized numerous paradigms of condensed matter physics, where control over interactions has crucially been afforded by tunable Feshbach resonances. So far, the characterization of these Feshbach resonances has almost exclusively relied on experiments in the threshold regime near zero energy. Here, we use a laser-based collider to probe a narrow magnetic Feshbach resonance of rubidium above threshold. By measuring the overall atomic loss from colliding clouds as a function of magnetic field, we track the energy-dependent resonance position. At higher energy, our collider scheme broadens the loss feature, making the identification of the narrow resonance challenging. However, we observe that the collisions give rise to shifts in the center-of-mass positions of outgoing clouds. The shifts cross zero at the resonance and this allows us to accurately determine its location well above threshold. Our inferred resonance positions are in excellent agreement with theory. [ABSTRACT FROM AUTHOR]

The cancer microenvironment allows tumor cells to evade immune surveillance through a variety of mechanisms. While interferon-γ (IFNγ) is central to effective antitumor immunity, its effects on the microenvironment are not as clear and have in some cancers been shown to induce immune checkpoint ligands. The heterogeneity of these responses to IFNγ remains poorly characterized in desmoplastic malignancies with minimal inflammatory cell infiltration, such as pancreatic cancer (PC). Thus, the IFNγ response within and on key cells of the PC microenvironment was evaluated. IFNγ induced expression of human leukocyte antigen (HLA) class I and II on PC cell lines, primary pancreatic cancer epithelial cells (PPCE) and patient-derived tumor-associated stroma, concomitant with an upregulation of PDL1 in the absence of CD80 and CD86 expression. As expected, IFNγ also induced high levels of CXCL10 from all cell types. In addition, significantly higher levels of CXCL10 were observed in PC specimens compared to those from chronic pancreatitis, whereby intratumoral CXCL10 concentration was an independent predictor of poor survival. Immunohistochemical analysis revealed a subset of CXCR3-positive cancer cells in over 90 % of PC specimens, as well as on a subset of cultured PC cell lines and PPCE, whereby exposure to CXCL10 induced resistance to the chemotherapeutic gemcitabine. These findings suggest that IFNγ has multiple effects on many cell types within the PC microenvironment that may lead to immune evasion, chemoresistance and shortened survival. [ABSTRACT FROM AUTHOR]

Background: Recurrence after resection of pancreatic ductal adenocarcinoma (PDAC) is common, thus postoperative surveillance is critical for detection and treatment of recurrent disease. The development of biologically based techniques for early recurrence detection may enable more timely and effective treatment of such recurrences. Methods: Tumor fragments derived from patients who underwent potentially curative resection of PDAC were heterotopically implanted into NOD/SCID mice. Engraftment success rates and growth parameters were matched to clinicopathologic data, preoperative treatment status, and oncologic outcomes to correlate disease-free survival (DFS) and overall survival. Results: Seventy patients consented to participate with 56 (80 %) developing a mouse PDAC tumorgraft. Patients with successful engraftment had a shorter median DFS compared with patients whose tumorgrafts failed to engraft (9.8 vs. 40.9 mo, respectively; p < 0.01). Fifty patients received preoperative therapy with 36 (72 %) successful tumorgrafts from this cohort. On multivariate analysis, lymph node metastasis (hazard ratio [HR] 3, 95 % CI 1.4-6.7, p < 0.01) and successful engraftment (HR 5.8, 95 % CI 2-16.9, p < 0.01) were predictive of a shorter DFS in the preoperative therapy cohort. In patients who recurred, tumorgraft formation was identified at a median of 134.5 days before standard methods of radiographic recurrence detection ( p < 0.01). Conclusions: Patient-derived tumorgrafts from resected PDAC may potentially predict recurrence months before currently available surveillance modalities. This lead-time advantage may allow for earlier implementation or changes in therapy as successful engraftment, particularly in those having undergone preoperative therapy, may indicate a more biologically aggressive disease. [ABSTRACT FROM AUTHOR]

Abstract  This paper presents novel methods for producing transgenic animals, with a further emphasis on how these techniques may someday be applied in gene therapy. There are several passive methods for transgenesis, such as pronuclear microinjection (PNI) and Intracytoplasmic Sperm Injection-Mediated Transgenesis (ICSI-Tr), which rely on the repair mechanisms of the host for transgene (tg) insertion. ICSI-Tr has been shown to be an effective means of creating transgenic animals with a transfection efficiency of approximately 45% of animals born. Furthermore, because this involves the injection of the transgene into the cytoplasm of oocytes during fertilization, limited mosaicism has traditionally occurred using this technique. Current active transgenesis techniques involve the use of viruses, such as disarmed retroviruses which can insert genes into the host genome. However, these methods are limited by the size of the sequence that can be inserted, high embryo mortality, and randomness of insertion. A novel active method has been developed which combines ICSI-Tr with recombinases or transposases to increase transfection efficiency. This technique has been termed “Active Transgenesis” to imply that the tg is inserted into the host genome by enzymes supplied into the oocyte during tg introduction. DNA based methods alleviate many of the costs and time associated with purifying enzyme. Further studies have shown that RNA can be used for the transposase source. Using RNA may prevent problems with continued transposase activity that can occur if a DNA transposase is integrated into the host genome. At present piggyBac is the most effective transposon for stable integration in mammalian systems and as further studies are done to elucidate modifications which improve piggyBac’s specificity and efficacy, efficiency in creating transgenic animals should improve further. Subsequently, these methods may someday be used for gene therapy in humans. [ABSTRACT FROM AUTHOR]

We propose a method for transferring atoms to a target quantum state for a multilevel quantum system with sequentially increasing, but otherwise unknown, energy splitting. This is achieved with a feedback algorithm that processes off-resonant optical measurements of state populations during adiabatic rapid passage in real time. As a demonstration, we reliably perform the state transfer |F = 2,mF = 2〉 → |1,1〉 → |2,1〉 for a sample of ultracold 87Rb in the presence of a random external magnetic field. [ABSTRACT FROM AUTHOR]

Quantum mechanical scattering resonances for colliding particles occur when a continuum scattering state couples to a discrete bound state between them. The coupling also causes the bound state to interact with itself via the continuum and leads to a shift in the bound state energy, but, lacking knowledge of the bare bound state energy, measuring this self-energy via the resonance position has remained elusive. Here, we report on the direct observation of self-interaction by using a nano-eV atom collider to track the position of a magnetically-tunable Feshbach resonance through a parameter space spanned by energy and magnetic field. Our system of potassium and rubidium atoms displays a strongly non-monotonic resonance trajectory with an exceptionally large self-interaction energy arising from an interplay between the Feshbach bound state and a different, virtual bound state at a fixed energy near threshold. [ABSTRACT FROM AUTHOR]