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To investigate the risk factors associated with the development of thrombocytopenia, and define the thresholds of efficacy and safety in critically ill patients who received linezolid therapy. A retrospective study was performed in critically ill patients treated with linezolid. Risk factors associated with thrombocytopenia were identified via medical records and trough levels (C min ) measured during linezolid treatment. By establishing a logistic model, the risks were predicted by the receiver operating characteristic (ROC) curve and the thresholds of efficacy and safety were identified in the patients. Logistic analysis showed that, weight (OR = 0.906; 95 % CI, 0.839–0.978; P  = 0.011), baseline platelet count (OR = 0.989; 95 % CI, 0.977–1.000; P  = 0.049), C min (OR = 1.545; 95 % CI, 1.203–1.983; P  = 0.001), and APACHE II score (OR = 1.130; 95 % CI, 1.003–1.273; P  = 0.044) were significant factors for linezolid-associated thrombocytopenia. The area under the ROC curve of the combined predictor was larger based on the above factors. When the Youden index was the maximum, the best optimal cut-off point was 205.6 on the ROC curve; when C min  ≥ 2 mg/L, the probability of bacterial eradication was more than 80 %; when C min  ≥ 6.3 mg/L, the probability of thrombocytopenia was more than 50 %. In clinical practice, when the calculating results of the combined predictor ≤205.6, the risk of the development of thrombocytopenia may be higher. Furthermore, maintenance of C min between 2 and 6.3 mg/L over time may be helpful in retaining appropriate efficacy and reducing the associated thrombocytopenia.

The current therapies to treat hepatitis B virus (HBV) infection are limited. Recently, clustered regularly interspaced short palindromic repeat (CRISPR) systems, originally identified in bacteria and archaea, have been found to consist of an RNA-based adaptive immune system that degrades complimentary sequences of invading plasmids and viruses. Here, we studied the effects of the CRISPR/CRISPR-associated Cas9 system that was targeted to the surface antigen (HBsAg)-encoding region of HBV, both in a cell culture system and in vivo . The HBsAg levels in the media of the cells and in the sera of mice were analyzed by a quantitative enzyme-linked immunosorbent assay. The HBV DNA levels were assessed by quantitative PCR and HBsAg expression in mouse livers was assessed by an immunohistochemical assay. The amount of HBsAg secreted in the cell culture and mouse serum was reduced by CRISPR/Cas9 treatment. Immunohistochemistry analyses showed almost no HBsAg-positive cells in the liver tissue of CRISPR/Cas9-S1+X3-treated mice. The CRISPR/Cas9 system efficiently produced mutations in HBV DNA. Thus, CRISPR/Cas9 inhibits HBV replication and expression in vitro and in vivo and may constitute a new therapeutic strategy for HBV infection.

Despite accounting for a significant portion of the Earth’s prokaryotic biomass, controls on the abundance and biodiversity of microorganisms residing in the continental subsurface are poorly understood. To redress this, we compiled cell concentration and microbial diversity data from continental subsurface localities around the globe. Based on considerations of global heat flow, surface temperature, depth and lithology, we estimated that the continental subsurface hosts 2 to 6 × 1029 cells and found that other variables such as total organic carbon and groundwater cellular abundances do not appear to be predictive of cell concentrations in the continental subsurface. Although we were unable to identify a reliable predictor of species richness in the continental subsurface, we found that bacteria are more abundant than archaea and that their community composition was correlated to sample lithology. Using our updated continental subsurface cellular estimate and existing literature, we estimate that the total global prokaryotic biomass is approximately 23 to 31 Pg of carbon C (PgC), roughly 4 to 10 times less than previous estimates.

Air pollution is a major environmental concern during all seasons in the megacity of Beijing, China. Here we present the results from a winter study that was conducted from 21 November 2011 to 20 January 2012 with an Aerodyne Aerosol Chemical Speciation Monitor (ACSM) and various collocated instruments. The non-refractory submicron aerosol (NR-PM1) species vary dramatically with clean periods and pollution episodes alternating frequently. Compared to summer, wintertime submicron aerosols show much enhanced organics and chloride, which on average account for 52% and 5%, respectively, of the total NR-PM1 mass. All NR-PM1 species show quite different diurnal behaviors between summer and winter. For example, the wintertime nitrate presents a gradual increase during daytime and correlates well with secondary organic aerosol (OA), indicating a dominant role of photochemical production over gas–particle partitioning. Positive matrix factorization was performed on ACSM OA mass spectra, and identified three primary OA (POA) factors, i.e., hydrocarbon-like OA (HOA), cooking OA (COA), and coal combustion OA (CCOA), and one secondary factor, i.e., oxygenated OA (OOA). The POA dominates OA during wintertime, contributing 69%, with the other 31% being SOA. Further, all POA components show pronounced diurnal cycles with the highest concentrations occurring at nighttime. CCOA is the largest primary source during the heating season, on average accounting for 33% of OA and 17% of NR-PM1. CCOA also plays a significant role in chemically resolved particulate matter (PM) pollution as its mass contribution increases linearly as a function of NR-PM1 mass loadings. The SOA, however, presents a reverse trend, which might indicate the limited SOA formation during high PM pollution episodes in winter. The effects of meteorology on PM pollution and aerosol processing were also explored. In particular, the sulfate mass is largely enhanced during periods with high humidity because of fog processing of high concentration of precursor SO2. In addition, the increased traffic-related HOA emission at low temperature is also highlighted.

Base-induced elimination (E2) and bimolecular nucleophilic substitution (S N 2) reactions are of significant importance in physical organic chemistry. The textbook example of the retardation of S N 2 reactivity by bulky alkyl substitution is widely accepted based on the static analysis of molecular structure and steric environment. However, the direct dynamical evidence of the steric hindrance of S N 2 from experiment or theory remains rare. Here, we report an unprecedented full-dimensional (39-dimensional) machine learning-based potential energy surface for the 15-atom F − + (CH 3 ) 3 CI reaction, facilitating the reliable and efficient reaction dynamics simulations that can reproduce well the experimental outcomes and examine associated atomic-molecular level mechanisms. Moreover, we found surprisingly high “intrinsic” reactivity of S N 2 when the E2 pathway is completely blocked, indicating the reaction that intends to proceed via E2 transits to S N 2 instead, due to a shared pre-reaction minimum. This finding indicates that the competing factor of E2 but not the steric hindrance determines the small reactivity of S N 2 for the F − + (CH 3 ) 3 CI reaction. Our study provides new insight into the dynamical origin that determines the intrinsic reactivity in gas-phase organic chemistry. Base-induced elimination (E2) and bimolecular nucleophilic substitution (SN2) are of significant importance in physical organic chemistry. Here, the authors show that the competing factor of E2 as opposed to steric hindrance determines the low reactivity of SN2 in the F − + (CH 3 ) 3 CI reaction.

Pinpointing the role of geometric phaseDuring chemical reactions, electrons usually rearrange more quickly than nuclei. Thus, theorists often adopt an adiabatic framework that considers vibrational and rotational dynamics within single electronic states. Near the regime where two electronic states intersect, the dynamics get more complicated, and a geometric phase factor is introduced to maintain the simplifying power of the adiabatic treatment. Yuan et al. conducted precise experimental measurements that validate this approach. They studied the elementary H + HD reaction at energies just above the intersection of electronic states and observed angular oscillations in the product-state cross sections that are well reproduced by simulations that include the geometric phase.Science, this issue p. 1289Theory has established the importance of geometric phase (GP) effects in the adiabatic dynamics of molecular systems with a conical intersection connecting the ground- and excited-state potential energy surfaces, but direct observation of their manifestation in chemical reactions remains a major challenge. Here, we report a high-resolution crossed molecular beams study of the H + HD → H2 + D reaction at a collision energy slightly above the conical intersection. Velocity map ion imaging revealed fast angular oscillations in product quantum state–resolved differential cross sections in the forward scattering direction for H2 products at specific rovibrational levels. The experimental results agree with adiabatic quantum dynamical calculations only when the GP effect is included.

Intracranial aneurysms (IA) are local dilatations in cerebral arteries that predominantly affect the circle of Willis. Occurring in approximately 2–5% of adults, these weakened areas are susceptible to rupture, leading to subarachnoid hemorrhage (SAH), a type of hemorrhagic stroke. Due to its early age of onset and poor prognosis, SAH accounts for > 25% of years lost for all stroke victims under the age of 65. In this review, we describe the cerebrovascular pathology associated with intracranial aneurysms. To understand IA genetics, we summarize syndromes with elevated incidence, genome-wide association studies (GWAS), whole exome studies on IA-affected families, and recent research that established definitive roles for Thsd1 (Thrombospondin Type 1 Domain Containing Protein 1) and Sox17 (SRY-box 17) in IA using genetically engineered mouse models. Lastly, we discuss the underlying molecular mechanisms of IA, including defects in vascular endothelial and smooth muscle cells caused by dysfunction in mechanotransduction, Thsd1/FAK (Focal Adhesion Kinase) signaling, and the Transforming Growth Factor β (TGF-β) pathway. As illustrated by THSD1 research, cell adhesion may play a significant role in IA.

Recent experiments have demonstrated that vibrational strong coupling (VSC) between molecular vibrations and the optical cavity field can modify vibrational energy transfer (VET) processes in molecular systems. However, the underlying mechanisms and the behavior of individual molecules under collective VSC remain largely incomplete. In this work, we combine state-of-the-art quantum vibrational spectral calculation, quantum wavepacket dynamics simulations, and ab initio machine-learning potential to elucidate how the vibrational dynamics of water OH stretches can be altered by VSC. Taking the ( H 2 O ) 21 -cavity system as an example, we show that the collective VSC breaks the localization picture, promotes the delocalization of OH stretches, and opens new intermolecular vibrational energy pathways involving both neighboring and remote water molecules. The manipulation of the VET process relies on the alignment of the transition dipole moment orientations of the corresponding vibrational states. The emergence of new energy transfer pathways is found to be attributed to cavity-induced vibrational resonance involving OH stretches across different water molecules, along with alterations in mode coupling patterns. Vibrational strong coupling (VSC) can alter energy exchange in molecules. Here, authors show that VSC delocalizes OH stretches in water, enhancing intermolecular energy transfer rates and enabling new pathways via cavity-induced resonances.

Objective This study aimed to investigate the clinical characteristics and long-term prognosis of mycoplasma pneumoniae pneumonia (MPP)-associated thrombosis and to gain a better understanding of the diagnosis and treatment of the disease. Methods The medical records of 14 children with MPP-associated thrombosis between January 2016 and April 2020 were retrospectively reviewed at the Tianjin Children’s Hospital. Results The ages of the patients ranged from 3 to 12 years old. Among the 14 cases, there were five cases of pulmonary embolism, two cases of cerebral infarction, one case of splenic infarction, one case of cardiac embolism, two cases of cardiac embolism with comorbid pulmonary embolism, one case of internal carotid artery and pulmonary embolism, one case of combined internal carotid artery and the cerebral infarction, and one case combined cardiac embolism and lower limb artery embolism. All cases had elevated D-dimer levels. After thrombolysis and anticoagulation therapy, three cases with cerebral embolism still suffered from neurological sequelae. In contrast, the remaining cases did not develop complications. Conclusion MPP-associated thrombosis can occur in any vessel of the body. Thrombosis-associated symptoms may be complex and non-specific. Elevated D-dimer levels in a child with refractory mycoplasma pneumoniae pneumonia should raise suspicion of thrombosis. The long-term prognosis of thrombosis was favorable after the timely administration of anticoagulant therapy.

Ly et al.  establish a method to selectively inactivate the centromere of the Y chromosome to follow chromosome shattering and micronuclei formation through several cell cycles, and suggest re-ligation of chromosome fragments is dependent on non-homologous end joining. Chromosome missegregation into a micronucleus can cause complex and localized genomic rearrangements 1 , 2 known as chromothripsis 3 , but the underlying mechanisms remain unresolved. Here we developed an inducible Y centromere-selective inactivation strategy by exploiting a CENP-A/histone H3 chimaera to directly examine the fate of missegregated chromosomes in otherwise diploid human cells. Using this approach, we identified a temporal cascade of events that are initiated following centromere inactivation involving chromosome missegregation, fragmentation, and re-ligation that span three consecutive cell cycles. Following centromere inactivation, a micronucleus harbouring the Y chromosome is formed in the first cell cycle. Chromosome shattering, producing up to 53 dispersed fragments from a single chromosome, is triggered by premature micronuclear condensation prior to or during mitotic entry of the second cycle. Lastly, canonical non-homologous end joining (NHEJ), but not homology-dependent repair, is shown to facilitate re-ligation of chromosomal fragments in the third cycle. Thus, initial errors in cell division can provoke further genomic instability through fragmentation of micronuclear DNAs coupled to NHEJ-mediated reassembly in the subsequent interphase.