Transplantation in Adult Patients with Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis: Yes or No?

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome characterized by aberrant immunological activity with a dismal prognosis. Epstein-Barr virus-associated HLH (EBV-HLH) is the most common type among adults. Patients with EBV infection to B cells could benefit from rituximab, whereas lethal outcomes may occur in patients with EBV infection to T cells, nature killer (NK) cells, or multilineages. The necessity of allogeneic hematopoietic stem cell transplantation (HSCT) in adult EBV-HLH patients remains controversial. A total of 356 adult EBV-HLH patients entered this study. Eighty-eight received HSCT under medical recommendation. Four received salvage HSCT. The 5-year overall survival (OS) rate of HSCT group was 48.7% (vs 16.2% in non-transplanted patients, p<0.001). There was no difference in OS between patients who received transplantation at first complete remission (CR1) and those at first partial remission (PR1) nor between patients at CR1 and CR2. Patients who received transplantation at PR2 had inferior survival. The rate of reaching CR2 was significantly higher in patients with CR1 than PR1 (p=0.014). Higher sCD25 levels, higher EBV-DNA loads in plasma after HSCT, poorer remission status, more advanced acute graft-versus-host disease (aGVHD), and the absence of localized chronic GVHD (cGVHD) were associated with an inferior prognosis (p<0.05). HSCT improved the survival of adult EBV-HLH significantly. For patients who achieved PR after initial treatment, HSCT was recommended. A wait-and-see strategy could be adopted for patients who achieved CR after initial treatment, but with the risk of failing to achieve a second CR.

In Situ TEM Characterization and Modulation for Phase Engineering of Nanomaterials.

Solid-state phase transformation is an intriguing phenomenon in crystalline or noncrystalline solids due to the distinct physical and chemical properties that can be obtained and modified by phase engineering. Compared to bulk solids, nanomaterials exhibit enhanced capability for phase engineering due to their small sizes and high surface-to-volume ratios, facilitating various emerging applications. To establish a comprehensive atomistic understanding of phase engineering, in situ transmission electron microscopy (TEM) techniques have emerged as powerful tools, providing unprecedented atomic-resolution imaging, multiple characterization and stimulation mechanisms, and real-time integrations with various external fields. In this Review, we present a comprehensive overview of recent advances in in situ TEM studies to characterize and modulate nanomaterials for phase transformations under different stimuli, including mechanical, thermal, electrical, environmental, optical, and magnetic factors. We briefly introduce crystalline structures and polymorphism and then summarize phase stability and phase transformation models. The advanced experimental setups of in situ techniques are outlined and the advantages of in situ TEM phase engineering are highlighted, as demonstrated via several representative examples. Besides, the distinctive properties that can be obtained from in situ phase engineering are presented. Finally, current challenges and future research opportunities, along with their potential applications, are suggested.

A convenient and practical index for predicting the induction response in adult patients with hemophagocytic lymphohistiocytosis: ferritin/platelet ratio.

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome with high mortality rate. The response to induction therapy is an important factor affecting survival. The purpose is to investigate laboratory predictors for induction response in adult patients with HLH, which are convenient, practical, and timeliness. Clinical data from January 2017 to December 2020 was retrospectively analyzed, and 269 patients were included. Patients were divided into remission and non-remission groups according to their induction response, 177 in the remission group, and 92 in the non-remission group. We reviewed general characteristics and analyzed the predictive value of serum ferritin, triglycerides, alanine aminotransferase (ALT), and blood cells before and 1-4 weeks after induction therapy for induction response by univariate analysis, ROC curves, etc. There was a correlation between serum ferritin, ALT, leukocytes, neutrophils, hemoglobin, platelets, and induction response (P < 0.05). Serum ferritin and platelets 1-4 weeks after induction therapy, respectively, might be a good predictor for induction response in adults with HLH, with AUC values close to or greater than 0.7. We established a new clinical model of the ferritin/platelet ratio. The results showed that the ferritin/platelet ratio at 1-4 weeks after induction therapy might be a practical index for predicting induction response, which significantly improved the area under the ROC curve (AUC > 0.75). Patients with a ferritin/platelet ratio > 16.08 at 2 weeks after induction therapy may have a relatively poor induction response. Ferritin/platelet ratio after induction therapy can be a good predictor for induction response in adult patients with HLH.

Dual-Channel Fluorescent Probe for the Detection of Peroxynitrite and Glutathione in Mitochondria: Accurate Discrimination of Inflammatory and Progressing Tumor Cells.

Distinguishing between normal, inflammatory, and progressing tumor cells plays a vital role in early diagnoses and clinical studies. The simultaneous quantification of multiple biomarkers in cells can reveal cellular heterogeneity, which contributes to the discrimination of different types of cells. Herein, a dual-channel fluorescent probe has been developed for monitoring peroxynitrite (ONOO-) and glutathione (GSH) to accurately discriminate normal cells, inflammatory cells, and progressing cancer cells. The probe can monitor exogenous and endogenous mitochondrial GSH and ONOO- in living cells and zebrafish by green (530 nm, G530) and red (630 nm, R630) emission based on its good selectivity and low biotoxicity. GSH and ONOO- are visualized via fluorescence imaging, and the corresponding output signals can be employed to differentiate nontumorigenic, malignant, and metastatic breast cells in cocultured cells. Furthermore, the accurate discrimination among normal, inflammatory, and cancerous cells is achieved through the changes in the dual-channel fluorescence signal, which shows great potential for the diagnosis of inflammation and cancer diseases.

Comorbidity of Post-Traumatic Stress Disorder and Alcohol Use Disorder: Animal Models and Associated Neurocircuitry.

Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) are prevalent neuropsychiatric disorders and frequently co-occur concomitantly. Individuals suffering from this dual diagnosis often exhibit increased symptom severity and poorer treatment outcomes than those with only one of these diseases. Lacking standard preclinical models limited the exploration of neurobiological mechanisms underlying PTSD and AUD comorbidity. In this review, we summarize well-accepted preclinical model paradigms and criteria for developing successful models of comorbidity. We also outline how PTSD and AUD affect each other bidirectionally in the nervous nuclei have been heatedly discussed recently. We hope to provide potential recommendations for future research.

Rational Modulation of the Luminescence of Upconversion Nanomaterials with Phycocyanin for the Sensing and Imaging of Myeloperoxidase during an Inflammatory Process.

Myeloperoxidase (MPO) is a heme peroxidases protein associated with many inflammation-related diseases. Although many fluorescent probes have been constructed for the assessment of MPO activity, it still remains a challege to develop a nanoprobe for highly sensitive biosensing and high-resolution bioimaging in biological system. In this work, we developed a novel luminescent nanoprobe based on upconversion nanoparticles (UCNPs) conjugated with phycocyanin (PC), which could detect the fluctuation of MPO. By grafting PC onto the surface of UCNPs through amidation reaction, the luminescence of UCNPs is quenched by PC via energy transfer. Due to the specific recognition by PC, the nanoprobe can be used for sensitive evaluation the bioactivity of MPO. The nanoprobe based on PC-UCNPs has been successfully applied for the bioimaging of MPO in living cells and an inflammatory process by taking an acute liver injury mouse as a model.

Is returning farmland to forest an effective measure to reduce phosphorus delivery across distinct spatial scales?

As one typical land use change, the mechanism of returning farmland to forests (RFF) on nonpoint source pollution (NPS) is not clear, especially at multiple spatial scales. In this study, by using the Soil and Water Assessment Tool (SWAT), the changes in several flow-related and NPS-related indicators across several nested catchments were quantified and compared in the Three Gorges Reservoir Region, China. The results indicated that RFF could reduce the total flow and total phosphorus (TP), which are higher in the dry season (41% and 79%, respectively) than in the wet season (21% and 47%, respectively) at the watershed with a total area of 2423.74 km2. In comparison, RFF has a larger impact on the baseflow index during the wet season (367.02%) than during the dry season (166.54%). The results also indicated that a spatial scaling effect did exist, while the reduction in TP increased from 24.57% to 48.46% as the drainage area increased from 65.92 km2 to 2104.35 km2. Specific thresholds of RFF efficiency were also observed (approximately 2000 km2 for the study area). It is suggested that other source control measures could supplement RFF by stabilizing the efficiency of RFF across different spatial scales. The results of this study could provide valuable suggestions for land use development and water quality protection, especially for large, complex watersheds.

[Chemical constituents from roots of Rubus parvifolius].

OBJECTIVE: To investigate the chemical constituents from the roots of Rubus parvifolius. METHODS: The chemical constituents were isolated by silica gel column chromatography, Sephadex LH-20, as well as preparative high performance liquid chromatography. Their structures were identified on the basis of physicochemical properties and NMR analysis. RESULTS: Six comounds were isolated and identified as 3-O-Acetyl-11α, 12α-epoxy-oleanan-28,ß-olide( I ) ,3-O-Acetyl-pomolic acid( II ), Ursolic acid( Ill),Ursolic acid acetate (1V ), Euscaphic acid ( V) and ß-Sitosterol ( VI). CONCLUSION: Compounds I , II and IV are isolated from Rubus parvifolius for the first time.

Effects of temperature cycles on human thermal comfort in built environment under summer conditions.

Dynamic temperature control strategies are feasible for enhancing energy flexibility and reducing energy consumption in buildings. However, guidelines for designing such dynamic thermal environments are lacking. In this study, 30 participants were recruited to undergo four experimental cycles formed by combining two temperature ranges (25-28 °C and 26-29 °C) and two temperature change rates (3 °C/h and 6 °C/h). Variations in the subjective perception and physiological responses with time were recorded throughout the experiments. The participants reported cooler thermal sensation and better thermal comfort for the same temperature during the ramp-down phase than during the ramp-up phase, which was more pronounced at faster temperature changes. The limits on temperature variations in the current standards underestimate the thermal acceptability of people. Although the temperature cycles exceeded the limits in the standards, sustained thermal comfort and high thermal acceptability were achieved when the temperature changed within 25-28 °C. At a rapid 6 °C/h change rate, the thermal sensation briefly deviated from the comfort zone when Top changed within 26-29 °C, suggesting that the limits should be set relative to the temperature change span. The comfortable temperature ranges for change rates of 3 °C/h and 6 °C/h in summer conditions were 22.8-28.7 °C and 22.8-28.4 °C, respectively, which are broader than the recommended indoor temperature range for summer in the Chinese standard. These findings indicate the potential of temperature variations to extend the thermal comfort zones while consuming less energy without requiring additional cooling devices.

Rejuvenation as the origin of planar defects in the CrCoNi medium entropy alloy.

High or medium- entropy alloys (HEAs/MEAs) are multi-principal element alloys with equal atomic elemental composition, some of which have shown record-breaking mechanical performance. However, the link between short-range order (SRO) and the exceptional mechanical properties of these alloys has remained elusive. The local destruction of SRO by dislocation glide has been predicted to lead to a rejuvenated state with increased entropy and free energy, creating softer zones within the matrix and planar fault boundaries that enhance the ductility, but this has not been verified. Here, we integrate in situ nanomechanical testing with energy-filtered four-dimensional scanning transmission electron microscopy (4D-STEM) and directly observe the rejuvenation during cyclic mechanical loading in single crystal CrCoNi at room temperature. Surprisingly, stacking faults (SFs) and twin boundaries (TBs) are reversible in initial cycles but become irreversible after a thousand cycles, indicating SF energy reduction and rejuvenation. Molecular dynamics (MD) simulation further reveals that the local breakdown of SRO in the MEA triggers these SF reversibility changes. As a result, the deformation features in HEAs/MEAs remain planar and highly localized to the rejuvenated planes, leading to the superior damage tolerance characteristic in this class of alloys.

Ubiquitous short-range order in multi-principal element alloys.

Recent research in multi-principal element alloys (MPEAs) has increasingly focused on the role of short-range order (SRO) on material performance. However, the mechanisms of SRO formation and its precise control remain elusive, limiting the progress of SRO engineering. Here, leveraging advanced additive manufacturing techniques that produce samples with a wide range of cooling rates (up to 107 K s-1) and an enhanced semi-quantitative electron microscopy method, we characterize SRO in three CoCrNi-based face-centered-cubic (FCC) MPEAs. Surprisingly, irrespective of the processing and thermal treatment history, all samples exhibit similar levels of SRO. Atomistic simulations reveal that during solidification, prevalent local chemical order arises in the liquid-solid interface (solidification front) even under the extreme cooling rate of 1011 K s-1. This phenomenon stems from the swift atomic diffusion in the supercooled liquid, which matches or even surpasses the rate of solidification. Therefore, SRO is an inherent characteristic of most FCC MPEAs, insensitive to variations in cooling rates and even annealing treatments typically available in experiments.

Improvement of thermal perceptions and physiological responses using torso heating under short-term cold exposure.

Short-term cold exposure (<1 h) may adversely affect human thermal comfort and health. Few studies have investigated the effectiveness of body heating in providing thermal protection to the torso against sharp temperature decreases, as well as the optimal operation modes of torso heating equipment. In this study, 12 male subjects were acclimatised in a room at 20 °C, then exposed to a cold environment at -2.2 °C, and finally returned to the room for recovery; each phase lasted 30 min. During cold exposure, they wore uniform clothing with an electrically heated vest (EHV) operated under these modes: no heating (NH), stage-regulated heating (SH), and intermittent alternating heating (IAH). Variations in subjective perceptions, physiological responses, and temperatures set for heating were recorded during the experiments. Torso heating mitigated the adverse effects of the large temperature down-step and continuous cold exposure on thermal perception and decreased the occurrence of three symptoms: cold hands or feet, running or stuffy noses, and shivering during cold exposure. After torso heating, the same skin temperature of the non-directly heated parts corresponded to a higher local thermal sensation, which was attributed to an indirect effect of the improved overall thermal state. The IAH mode could achieve thermal comfort at a reduced energy level, and it outperformed SH in subjective perception enhancement and self-reported symptom relief at lower heating temperatures. Additionally, under the same heating setting temperatures and power capacity, it could achieve an approximately 50 % longer usage time than SH could. The results suggest that intermittent heating protocol can be an efficient way to achieve thermal comfort and energy savings for personal heating devices.

An erythrocyte membrane-camouflaged fluorescent covalent organic framework for starving/nitric oxide/immunotherapy of triple-negative breast cancer.

It is a great challenge to effectively treat triple-negative breast cancer (TNBC) due to lack of therapeutic targets and drug resistance of systemic chemotherapy. Rational design of nanomedicine with good hemocompatibility is urgently desirable for combination therapy of TNBC. Herein, an erythrocyte membrane-camouflaged fluorescent covalent organic framework (COF) loaded with an NO donor (hydroxyurea, Hu), glucose oxidase (GOx) and cytosine-phosphate-guanine oligonucleotides (CPG) (COF@HGC) was developed for imaging-guided starving/nitric oxide (NO)/immunization synergistic treatment of TNBC. The substances of HGC are easily co-loaded onto the COF due to the ordered pore structure and large surface area. And a folic acid-modified erythrocyte membrane (FEM) is coated on the surface of COF@HGC to improve targeted therapy and haemocompatibility. When COF@HGC@FEM is internalized into tumor cells, hemoglobin (Hb) on FEM and GOx loaded on the COF can trigger cascade reactions to kill tumor cells due to the simultaneous production of NO and exhaustion of glucose. Meanwhile, the COF with excellent fluorescence properties can be used as a self-reporter for bioimaging. Furthermore, the CPG can reprogram tumor-associated macrophages from tumor-supportive phenotype to anti-tumor phenotype and enhance immunotherapy. Through the "three-in-one" strategy, the biomimetic nanoplatform can effectively inhibit tumor growth and reprogram the tumor immunosuppression microenvironment in the TNBC mouse model.

Serum sCD25/ferritin ratio combined with MCP-1 is a valid predictor for identifying LAHS with HLH as the first manifestation.

PURPOSE: Lymphoma-associated haemophagocytic syndrome (LAHS) is a group of malignant diseases with rapid progression and a high mortality rate. Our study aimed to discover the significance of serum sCD25/ferritin ratio as well as cytokines in assisting the diagnosis of LAHS. METHODS: We retrospectively analyzed the clinical data of 82 patients with LAHS with hemophagocytic lymphohistiocytosis (HLH) as the first manifestation and divided them into B-LAHS group and T/NK-LAHS group according to lymphoma pathological diagnosis for comparison. And patients with LAHS were divided into responding group, non-responding group according to the assessment of efficacy after receiving DEP/L-DEP induction therapy for 2 weeks to compare possible valuable indicators. RESULTS: Serum sCD25/ferritin ratio and MCP-1 levels were significantly different between B-LAHS and T/NK-LAHS groups (P = 0.001, P = 0.022). An sCD25/ferritin ratio > 7.8 tended to suggest a diagnosis of B-LAHS (AUC = 0.71, 95% CI: 0.596-0.823), and the sCD25/ferritin ratio had better predictive value when combined with MCP-1 (AUC = 0.81, 95% CI: 0.699-0.922). The sCD25/ferritin ratio was also significantly different between the two groups responding or not responding to induction therapy (P = 0.002), yielding an optimal cutoff value of 11.48. An sCD25/ferritin ratio > 11.48 tended to suggest that the patient's LAHS was responsive to induction therapy. CONCLUSION: Our study reveals that serum sCD25/ferritin ratio combined with MCP-1 is a valid predictor for identifying LAHS with HLH as the first manifestation and may assist in predicting whether the lymphoma is of B-cell or T/NK-cell origin. The sCD25/ferritin ratio can also be used to predict the early response of LAHS after induction therapy.

Dye-sensitized rare-earth-doped nanoprobe for simultaneously enhanced NIR-II imaging and precise treatment of bacterial infection.

Methicillin-resistant Staphylococcus aureus (MRSA) is responsible for causing life-threatening infections that result in high morbidity and mortality rates. The development of advanced imaging and therapeutic methods for in vivo diagnosis and treatment of MRSA infections remains challenging. Here, we develop a hybrid nanoplatform based on rare-earth-doped nanoparticles (RENPs) sensitized by a moiety-engineered near-infrared (NIR) TPEO-820 dye and with a ZIF-8 layer that incorporates CysNO, a photochemically triggered nitric oxide donor. We then use the hybrid for both NIR-II bioimaging and photoactivatable treatment of MRSA-infected wounds. We show that the NIR dye sensitization leads to an 8.5-fold enhancement of the downshifting emission and facilitates deep-tissue NIR-II imaging of bacterial infections. Moreover, the sensitization strategy enhances the UV emission of RENPs by two orders of magnitude, leading to the efficiently controllable release of nitric oxide for effective disinfection of MRSA in vitro and in vivo. The hybrid nanoplatform thus offers promising opportunities for simultaneous localization and controllable treatment of MRSA. STATEMENT OF SIGNIFICANCE: Early detection and treatment of MRSA infections are crucial for reducing public health risks. It is a significant challenge that develops sensitive in vivo diagnosis and complete elimination of drug-resistant bacterial infections. Herein, a nanoplatform has been developed for photoactivatable therapy of MRSA infections and deep tissue NIR-II imaging. This platform utilizes lanthanide-doped rare earth nanoparticles (RENPs) that are sensitized by a moiety-engineered near-infrared (NIR) dye TPEO-820. The TPEO-820 sensitized RENPs exhibit 5 times increase in the release of NO concentration for MRSA treatment compared to unsensitized RENPs, enabling precise therapy of MRSA infection both in vitro and in vivo. Moreover, the platform demonstrates NIR-II luminescence in vivo, allowing for sensitive imaging in deep tissue for MRSA infection.

Temporal and spatial heterogeneity of indoor and outdoor temperatures and their relationship with thermal sensation from a global perspective.

People spend most of their time indoors. However, indoor temperature and individual thermal exposure are generally not considered in epidemiological studies of temperature and health. Based on the American Society of Heating, Refrigerating, and Air-Conditioning Engineers (ASHRAE) RP-884 Database, the ASHRAE Global Thermal Comfort Database II and the Chinese Thermal Comfort Database, this study first explored the relationship between outdoor temperature, indoor temperature and thermal sensation from a global perspective. Moreover, the potential influence of spatiotemporal heterogeneity on health studies was explored. A breakpoint was found at approximately 11.5 °C in the segmented regression of indoor and outdoor temperature, and the slope of the curve was greater when outdoor temperature was above the breakpoint (n = 67,896). Based on multi-group propensity score matching (PSM) and generalizedadditivemodels (GAM), spatiotemporal heterogeneity was found in the relationship between indoor and outdoor temperatures after adjusting for building type and year. Furthermore, the relationship between indoor temperature and thermal sensation was influenced by the outdoor temperature. This study highlights the importance of considering indoor temperature or individual thermal exposure in temperature-related health studies.

Rostromedial tegmental nucleus nociceptin/orphanin FQ (N/OFQ) signaling regulates anxiety- and depression-like behaviors in alcohol withdrawn rats.

Recent studies indicate that stimulation of the rostromedial tegmental nucleus (RMTg) can drive a negative affective state and that nociceptin/orphanin FQ (N/OFQ) may play a role in affective disorders and drug addiction. The N/OFQ precursor prepronociceptin encoding genes Pnoc are situated in RMTg neurons. To determine whether N/OFQ signaling contributes to the changes in both behavior phenotypes and RMTg activity of alcohol withdrawn (Post-EtOH) rats, we trained adult male Long-Evans rats, randomly assigned into the ethanol and Naïve groups to consume either 20% ethanol or water-only under an intermittent-access procedure. Using the fluorescence in situ hybridization technique combined with retrograde tracing, we show that the ventral tegmental area projecting RMTg neurons express Pnoc and nociceptin opioid peptide (NOP) receptors encoding gene Oprl1. Also, using the laser capture microdissection technique combined with RT-qPCR, we detected a substantial decrease in Pnoc but an increase in Oprl1 mRNA levels in the RMTg of Post-EtOH rats. Moreover, RMTg cFos expression is increased in Post-EtOH rats, which display anxiety- and depression-like behaviors. Intra-RMTg infusion of the endogenous NOP agonist nociceptin attenuates the aversive behaviors in Post-EtOH rats without causing any notable change in Naïve rats. Conversely, intra-RMTg infusion of the NOP selective antagonist [Nphe1]nociceptin(1-13)NH2 elicits anxiety- and depression-like behaviors in Naïve but not Post-EtOH rats. Furthermore, intra-RMTg infusion of nociceptin significantly reduces alcohol consumption. Thus, our results show that the deficiency of RMTg NOP signaling during alcohol withdrawal mediates anxiety- and depression-like behaviors. The intervention of NOP may help those individuals suffering from alcohol use disorders.

Comparative analysis on indoor and outdoor thermal comfort in transitional seasons and summer based on multiple databases: Lessons learnt from the outdoors.

In environments with similar physical parameters, thermal comfort and sensation feelings may differ indoors and outdoors. How indoor and outdoor thermal perception differ from each other remains unclear. This study compared and discussed 29,536 field survey data, including 19,191 sets of indoor data, and 10,345 sets of outdoor data, covering five Köppen climate zones during transitional seasons and summer. Indoor data points were collected from two databases: the ASHRAE Global Thermal Comfort II and the SCATs (Smart Controls and Thermal Comfort), while outdoor data points were collected from the RUROS database (Rediscovering the Urban Realm and Open Spaces) and five individual projects executed in Singapore, Hong Kong, Guangzhou, Changsha, and Tianjin. The concepts of neutral rate (NR) and comfort rate (CR) were developed to help categorize "neutral" and "comfort" across different studies. The results of this study show that people are less sensitive to changes in thermal environment outdoors than indoors. Moreover, thermal comfort cannot be simply treated as thermal neutral, particularly for outdoor spaces. Compared with MM (mixed-mode) and NV (naturally ventilated) spaces, outdoor space does not have the highest NR, but its CR is much higher, with a wide range of SET* (Standard Effective Temperature) corresponding to CR over 80 %, from 15.5 °C to 23.4 °C. In the Cfa (humid subtropical) climate zone, significantly higher CR are recorded for outdoor spaces, although the NR are similar or even lower than those of indoors. Natural thermal resources in the outdoor thermal environment may hold the key to extending indoor comfort ranges.