Browse Articles

Impact of acute respiratory distress syndrome on outcome in critically ill patients with liver cirrhosis

Abstract We investigated the occurrence and outcome of respiratory failure and ARDS in critically ill patients with liver cirrhosis. This is a retrospective analysis of patients with liver cirrhosis at an ICU during an 8-Year period. An assessment of acute on chronic liver failure as well as the presence and grade of ARDS within the first 72 h of admission to the ICU was performed. A total of 735 patients during the study period. Median age was 58 (50–69) years and 61% (n = 447) were male. 57% (n = 421) of the patients received mechanical ventilation (MV). Liver specific as well as ICU scores on admission were significantly higher in patients with MV. Necessity of vasopressor support (86%vs.25%, p < 0.001) and RRT (50%vs.11%, p < 0.001) was more frequent in patients with MV. The incidence of ARDS within the first 72 h of admission was 8% (n = 61). We observed a 28-day mortality or liver transplantation rate of 54% (n = 196) and 66% (n = 66%) in patients with MV and ARDS, respectively. After 90-days 63% (n = 226) with MV and 70% (n = 43) with ARDS were dead or received liver transplantation. ARDS is a prognostic factor for mortality in patients with liver cirrhosis admitted to the ICU. One out of ten critically ill cirrhotic patients develop ARDS within 72 h after admission. Although mortality rates are high initially critical care therapy should not be withheld and must be reevaluated regularly.

Transferrin promotes fatty acid oxidation and liver tumor growth through PHD2-mediated PPARα hydroxylation in an iron-dependent manner

Tumor cells reshape iron and lipid metabolism for their rapid proliferation. However, how tumor cells coordinate the interplay between tumor cell–specific iron homeostasis and lipid metabolism reprogramming to counteract energy shortages remains unclear. Here, we demonstrated that glucose deprivation in hepatocellular carcinoma (HCC) cells induced AMPK-dependent Transferrin S685 phosphorylation, which exposed Transferrin nuclear localization signal (NLS) for binding to importin α7 and subsequent nuclear translocation. Nucleus-translocated Transferrin interacts with PPARα and enhance its protein stability to increase fatty acid oxidation (FAO) upon glucose deprivation. Mechanistically, PPARα-associated Transferrin upregulates iron-dependent PHD2-mediated PPARα P87 hydroxylation and subsequently disrupts the binding of MDM2 to PPARα, therefore inhibiting MDM2-mediated PPARα ubiquitination and degradation. Reconstitution of Transferrin S685A and NLS mutation or knock-in expression of PPARα P87A inhibited PPARα-mediated FAO upon energy stress, enhanced HCC cell apoptosis, and impeded liver tumor growth in mice. Importantly, combined treatment with Transferrin pS685 blocking peptide suppressing AMPK-Transferrin-PPARα axis could synergize with a well-established AMPK activator Metformin to inhibit tumor growth. Additionally, Transferrin pS685-mediated PPARα P87 hydroxylation is positively correlated with PPARα expression levels in human HCC specimens and poor patient prognosis. These findings revealed a mechanism by which Transferrin can sense energy stress to promote the hydroxylation and protein stability of PPARα through iron-dependent activation of PHD2 and underscore the moonlighting function of Transferrin in lipid catabolism and liver tumor development.

Peridynamics analysis of crack propagation in concrete considering random aggregate distribution

Abstract The mechanical properties and fracture behavior of concrete are controlled by aggregate characteristics, and the distribution of aggregates is uncertain. Traditional studies on concrete crack propagation mainly conduct deterministic analysis based on the position and size of the aggregates, rarely considering the uncertainty of aggregate distribution. Based on the Peridynamics (PD) theory, random distribution functions are introduced to describe the geometric characteristics and positional parameters of concrete aggregates. Simulating the effect of random distribution of aggregates on concrete crack propagation by presetting random aggregates. For the first time, the Boundary Damage Ratio (BDR) is proposed to quantitatively describe the influence of cement mortar and aggregate on crack propagation, revealing the influence rules of random aggregate parameters on concrete damage provides a new method for studying concrete crack propagation. The research results show that the size and position of aggregates determine the crack propagation path during concrete failure. The BDR can indicate the quality of the concrete grading and the intensity of the aggregate’s guiding effect on crack propagation. It was found that the aggregate size and the BDR follow a Weibull distribution; the larger the aggregate size, the smaller the shape parameter.

Unconventional magnetic oscillations in a kagome Mott insulator

In metals, electrons in a magnetic field undergo cyclotron motion, leading to oscillations in physical properties called quantum oscillations. This phenomenon has never been seen in a robust insulator because there are no mobile electrons. We report an exception to this rule. We study a Mott insulator on a kagome lattice which does not order magnetically down to milli-Kelvin temperatures despite antiferromagnetic interactions. We observe a plateau at magnetization equal to 1 9 Bohr magneton per magnetic ion, accompanied by oscillations in the magnetic torque, reminiscent of quantum oscillations in metals. The temperature dependence obeys Fermi distribution. These phenomena are consistent with a quantum spin liquid state whose excitations are fermionic spinons with a Dirac-like spectrum coupled to an emergent gauge field.

Clinical and microbiological analysis of risk factors for breakthrough bloodstream infection during Tigecycline Therapy

A pentatomomorpha-specific salivary protein activates plant immunity and is critical for insect feeding

The stinkbug Riptortus pedestris , notorious for inducing soybean staygreen-like syndrome, employs a range of salivary proteins to manipulate the host plant for its benefit. Here, we show that RpSP1, a salivary protein specific to Pentatomomorpha, triggers plant defense responses in multiple plant species. RpSP1 interacts with and stabilizes a HSP40 family protein GmSPIP1 and is dependent on GmSPIP1 to induce cell death. We show that a critical 22-amino acid peptide within RpSP1 acts as an intracellular insect-derived elicitor. Furthermore, RpSP1 enhances insect-feeding efficiency. The dual functionality of RpSP1 is highlighted by the significant reduction of soybean staygreen-like syndrome following its overexpression in soybean plants or knockdown in insects. Our findings elucidate the complex molecular interactions between plants and herbivores, positioning RpSP1 as a crucial target for developing advanced pest management strategies with broad implications for agricultural biology.

Quality of routine malaria data captured at primary health facilities in the Hohoe Municipality, Ghana

Extremal structures with embedded prefailure indicators

Preemptive identification of potential failure under loading of engineering structures is a critical challenge. Our study presents an innovative approach to design built-in prefailure indicators within multiscale structural designs with optimized load carrying capabilities utilizing the design freedom of topology optimization. The indicators are engineered to visibly signal load conditions approaching the global critical buckling load at predefined locations. By showing noncritical local buckling when activated, the indicators provide early warning without compromising the overall structural integrity of the design. This proactive safety feature enhances structural reliability. The method is particularly beneficial for offshore wind turbines, where many sensors are located below sea level and are inaccessible for maintenance. By allowing the placement of indicators in accessible predetermined locations, our method can reduce the number of required sensors and improve structural health monitoring. Additionally, the potential use of memory overload indicators exploiting plasticity offers a reliable means of detecting overloads during offline periods. Experimental testing of 3D-printed designs confirms a strong correlation between measurements and numerical simulations, demonstrating the feasibility of creating structures that can signal the need for load reduction or maintenance at predetermined locations. This research contributes to the design of safer structures by introducing built-in early-warning failure systems.

Related studies on measuring the normal values of optic nerve sheath diameter in healthy Chinese adults based on CT scans

Cost-reduction strategy to culture patient derived bladder tumor organoids

SIV monoclonal antibody administration spanning treatment interruption in macaques delays viral rebound and selects escape variants

HIV-1 envelope broadly neutralizing antibodies represent a promising component of HIV-1 cure strategies. To evaluate the therapeutic efficacy of combination monoclonal antibodies (mAbs) in a rigorous nonhuman primate model, we tested different combinations of simian immunodeficiency virus (SIV) neutralizing mAbs in SIVmac251-infected rhesus macaques. Antiretroviral therapy-suppressed animals received anti-SIV mAbs targeting multiple Env epitopes spanning analytical treatment interruption (ATI) in 3 groups (n = 7 each): i) no mAb; ii) 4-mAb combination; and iii) 2-mAb combination. Each mAb was administered at 15 mg/kg, and both mAb-treated groups received ITS103.01, a highly potent CD4-binding site targeting antibody. mAb treatment delayed viral rebound, lowered rebound viremia setpoint and viral diversity, and extended animal lifespan. Compared to controls, for which viremia rebounded 2 wk following ATI, mAb infusion delayed rebound for both groups ( P = 0.0003). Animals that received the 4-mAb regimen rebounded 3 to 6 wk post-ATI while the 2-mAb regimen rebounded 5 to 22 wk post-ATI. Envelope escape mutations emerged in rebound virus of mAb-treated animals that abrogated neutralization by ITS103.01, the most potent in the cocktail. These data demonstrate in vivo antiviral activity of SIV mAbs in the context of ATI via immune pressure dominated by the most potent mAb and highlight their potential in adjunctive therapeutic studies.

Multicentre case-control study on the association between COVID-19 vaccines and neurological disorders (COVIVAX)

An analysis of the cultivation, consumption and composition of home-grown cannabis following decriminalisation in the Australian Capital Territory

Plastic responses to past environments shape adaptation to novel selection pressures

Phenotypic plasticity may pave the way for rapid adaptation to newly encountered environments. Although it is often contested, there is growing evidence that initial plastic responses of ancestral populations to new environmental cues may promote subsequent adaptation. However, we do not know whether plasticity to cues present in the ancestral habitat (past-cue plasticity) can facilitate adaptation to novel cues. Conceivably, this could occur if plastic responses are coincidentally optimal to both past and novel cues (i.e., are preadaptive) or if they are transferred to novel cues during adaptation. Past plastic phenotype values could also become fixed during adaptation to the new environment. To uncover the role of past-cue plasticity in adaptation, we tested gene expression plasticity responses of two parallel mine-waste-adapted Silene uniflora populations and their closest coastal relatives. Plants were exposed to the past and novel cues of salt and zinc, which revealed that during adaptation to mine waste, plasticity to salt diminishes. Despite this, our results show that ancestral plasticity to salt has a substantial impact on subsequent adaptation to zinc. For a third of genes that have evolved zinc plasticity in mine populations, salt plasticity has been transferred to the zinc response. Furthermore, a quarter of fixed expression differences between mine and coastal populations were similar to ancestral salt responses. Alongside evidence that ancestral plasticity to novel cues can facilitate adaptation, our results provide a clear indication that ancestral past-cue plasticity can also play a key role in rapid, parallel adaptation to novel habitats.

Chest CT characterization of children with necrotizing pneumonia due to Mycoplasma pneumoniae infection

Optimal strategies for correcting merotelic chromosome attachments in anaphase

Accurate chromosome segregation in mitosis depends on proper connections of sister chromatids, through microtubules, to the opposite poles of the early mitotic spindle. Transiently, many inaccurate connections are formed and rapidly corrected throughout the mitotic stages, but a small number of merotelic connections, in which a chromatid is connected to both spindle poles, remain lagging at the spindle’s equator in anaphase. Most of the lagging chromatids are eventually moved to one or the other pole, likely by a combination of microtubules’ turnover and the brute force of pulling by the microtubules’ majority from the one pole against the microtubules’ minority from the other pole. We use computer simulations from two stochastic models (1D and full 3D CellDynaMo model) combining force balances and microtubules’ dynamics for the lagging chromatids to investigate what maximizes the percentage of segregated laggards. We find that a) brute force tug-of-war with slow (< 0.0001 s −1 ) microtubules’ detachment rate can move asymmetric laggards to the poles in limited time, b) rapid (> 0.01 s −1 ) microtubules’ detachment rate leads to a significant loss of the laggards, and c) intermediate (~ 0.001 s −1 ) microtubules’ detachment rate ensures higher than 90% accuracy of segregation. The simulations also shed light on the waiting time required to correct the merotelic errors in anaphase and on the roles of chromatid-attached microtubule number and Aurora B–mediated, spatially graded regulation of microtubule kinetics in anaphase.

Prevalence and associated factors of epiretinal membrane using spectralis OCT in Fujian Eye Study

Errors are robustly tamed in cumulative knowledge processes

As knowledge accumulates in science and society in a distributed fashion, erroneous derivations can be introduced into the corpus of knowledge. Such derivations can compromise the validity of any units of knowledge that rely on them in the future. Can societal knowledge maintain some level of integrity given simple distributed error-checking mechanisms? In this paper, we investigate the following formulation of the question: assuming that a constant fraction of the new derivations is wrong, is it possible for simple error-checking mechanisms that apply when a new unit of knowledge is derived to maintain the integrity of the corpus of knowledge? This question was introduced by Ben-Eliezer et al. [“Is this correct? Let’s check!” in 14th Innovations in Theoretical Computer Science Conference (ITCS, 2023)], who gave a robust affirmative answer in a specific probabilistic model for knowledge accumulation. Namely, this model required that new units depend on just one existing unit and join the process according to a preferential attachment rule. In this work, we consider much more general families of processes of knowledge accumulation, where new units may depend on multiple existing units and join according to varied attachment mechanisms. We also consider models with a (random) fraction of insertions of adversarial nodes. We give a robust affirmative answer to the above question by showing that for all of these models, as long as many of the units follow simple local heuristics for checking a bounded number of units they depend on, all errors will be eventually eliminated.

Nonlinear relationship between hepatic steatosis index and reversion to normal glucose regulation in Chinese adults with prediabetes

Design of a light and Ca ²⁺ switchable organic–peptide hybrid

The design of organic–peptide hybrids has the potential to combine our vast knowledge of protein design with small molecule engineering to create hybrid structures with complex functions. Here, we describe the computational design of a photoswitchable Ca 2+ -binding organic–peptide hybrid. The designed molecule, designated Ca 2+ -binding switch (CaBS), combines an EF-hand motif from classical Ca 2+ -binding proteins such as calmodulin with a photoswitchable group that can be reversibly isomerized between a spiropyran (SP) and merocyanine (MC) state in response to different wavelengths of light. The MC/SP group acts both as a photoswitch as well as an optical sensor of Ca 2+ binding. Photoconversion of the SP to the corresponding MC unmasks an acidic phenol, which CaBS uses as an integral part of both its Ca 2+ -binding site as well as its tertiary and quaternary structure. By design, the SP state of CaBS is monomeric, while the Ca 2+ -bound form of the MC state is an obligate dimer, with two Ca 2+ -binding sites formed at the interface of a domain-swapped dimer. Thus, light and Ca 2+ were expected to serve as an “AND gate” that powers a change in backbone structure/dynamics, oligomerization state, and fluorescence properties of the designed molecule. CaBS was designed using Rosetta and molecular dynamics simulations, and experimentally characterized by nuclear magnetic resonance, isothermal titration calorimetry, and optical titrations. These data illustrate the potential of combining small molecule engineering with de novo protein design to develop sensors whose conformation, association state, and optical properties respond to multiple environmental cues.