Development of a novel humanized anti-TSLP monoclonal antibody HZ-1127 with anti-allergic diseases and cancer potential.

Thymic stromal lymphopoietin (TSLP) is a member of the IL-2 cytokine family and has been widely recognized as a master regulator of type 2 inflammatory responses at barrier surfaces. Recent studies found dysregulation of the TSLP-TSLP receptor (TSLPR) pathway is associated with the pathogenesis of not only allergic diseases but also a wide variety of cancers including both solid tumors and hematological tumors. Thus, the blockade of TSLP represents an attractive therapeutic strategy for allergic diseases and cancer. In this study, we report the development of a novel humanized anti-TSLP monoclonal antibody (mAb) HZ-1127. Binding affinity, specificity, and ability of HZ-1127 in inhibiting TSLP were tested. HZ-1127 selectively binds to the TSLP cytokine with high affinity and specificity. Furthermore, HZ-1127 dramatically inhibits TSLP-dependent STAT5 activation and is more potent than Tezepelumab, which is an FDA-approved humanized mAb against TSLP for severe asthma treatment in inhibiting TSLP-induced CCL17 and CCL22 chemokines secretion in human peripheral blood mononuclear cells. Our pre-clinical study demonstrates that HZ-1127 may serve as a potential therapeutic agent for allergic diseases and cancer.

Minimal Kinetic Model of Direct Air Capture of CO2 by Supported Amine Sorbents in Dry and Humid Conditions.

Dilute concentration (∼400 ppm) and humidity are two important factors in the direct air capture (DAC) of CO2 by supported sorbents. In this work, a minimal DAC CO2 adsorption-kinetics model was formulated for supported amine sorbents under dry and humid conditions. Our model fits well with a recent DAC experiment with supported amine sorbent in both dry and humid conditions. Temperature and flow rate effects on breakthrough curves were quantitatively captured, and increasing temperature led to faster CO2 adsorption kinetics. Moisture was shown to broaden the breakthrough curve with slower CO2 adsorption kinetics but significantly improve the uptake capacity. The present minimal model provides a versatile platform for kinetic modeling of the DAC of CO2 on supported amine and other chemisorption systems.

Posterior perforator tibial artery flaps for soft tissue defects of limbs: a retrospective cohort study.

PURPOSE: To investigate the clinical effect of posterior perforator tibial artery flaps on repairing soft tissue defects of limbs. METHODS: From June 2012 to June 2021, 14 cases of soft tissue defects of limbs were repaired with pedicled or free flaps of posterior perforator tibial artery. Among them, there were 9 cases of pedicled flaps and 5 cases of free flaps. The donor sites were closed directly or covered with skin grafting. The defects area varied from 3 × 5 cm to 7 × 16 cm. All cases were followed up for 1 year to 2 years. RESULTS: All flaps survived completely except 3 cases with distal end necrosis and the 3 cases healed after dressing change. There were not any other complications at both donor and recipient sites. Appearance of the recipient sites was close to the surrounding skin. All patients were satisfied with the results. CONCLUSION: Posterior perforator tibial artery flaps have the advantages of relatively simple technique, few damage, few complications and satisfying appearance. It is a good choice for soft tissue defects of limbs.

Highly stable localized surface plasmon resonance of Cu nanoparticles obtained via oxygen plasma irradiation.

Copper nanoparticles (CuNPs) possess strong localized surface plasmon resonance (LSPR) in visible light. However, CuNPs are not chemically stable in air, which has seriously hindered the applications based on the LSPR of CuNPs. We developed an artificial method to passivate CuNPs as Al naturally does in air, preventing the oxidation of CuNPs through swift oxidation of the surface atoms via oxygen plasma irradiation. A hemispheric core-shell structure of CuNPs uniformly covered by a dense CuO shell (CuNPs@d-CuO) was constructed. The 4 nm d-CuO shell can prevent CuNPs from further oxidation. As a result, the LSPR of the CuNPs is stable in air over 180 days.

Assessing intracellular and extracellular distribution of antibiotic resistance genes in the commercial organic fertilizers.

Compost-based organic fertilizers often contain high levels of antibiotic resistance genes (ARGs) and mobile genetic elements (MGEs). Previous studies focused on quantification of total ARGs and MGEs. For a more accurate risk assessment of the dissemination risk of antibiotic resistance, it is necessary to quantify the intracellular and extracellular distribution of ARGs and MGEs. In the present study, extracellular ARGs and MGEs (eARGs and eMGEs) and intracellular ARGs and MGEs (iARGs and iMGEs) were separately analyzed in 51 commercial composts derived from different raw materials by quantitative polymerase chain reaction (qPCR) and metagenomic sequencing. Results showed that eARGs and eMGEs accounted for 11-56% and 4-45% of the total absolute abundance of ARGs and MGEs, respectively. Comparable diversity, host composition and association with MGEs were observed between eARGs and iARGs. Contents of high-risk ARGs were similar between eARGs and iARGs, with high-risk ARGs in the two forms accounting for 6.7% and 8.2% of the total abundances, respectively. Twenty-four percent of the overall ARGs were present in plasmids, while 56.7% of potentially mobile ARGs were found to be associated with plasmids. Variation partitioning analysis, null model and neutral community model indicated that the compositions of both eARGs and iARGs were largely driven by deterministic mechanisms. These results provide important insights into the cellular distribution of ARGs in manure composts that should be paid with specific attention in risk assessment and management.

Quantifying carboxymethyl lysine and carboxyethyl lysine in human plasma: clinical insights into aging research using liquid chromatography-tandem mass spectrometry.

OBJECTIVE: The objective of this study was to establish a methodology for determining carboxymethyl lysine (CML) and carboxyethyl lysine (CEL) concentrations in human plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The test results were also used for clinical aging research. METHODS: Human plasma samples were incubated with aqueous perfluorovaleric acid (NFPA), succeeded by precipitation utilizing trichloroacetic acid, hydrolysis facilitated by hydrochloric acid, nitrogen drying, and ultimate re-dissolution utilizing NFPA, followed by filtration. Cotinine-D3 was added as an internal standard. The separation was performed on an Agela Venusil ASB C18 column (50 mm × 4.6 mm, 5 µm) with a 5 mmol/L NFPA and acetonitrile/water of 60:40 (v/v) containing 0.15% formic acid. The multiple reaction monitoring mode was used for detecting CML, CEL, and cotinine-D3, with ion pairs m/z 205.2 > 84.1 (for quantitative) and m/z 205.2 > m/z 130.0 for CML, m/z 219.1 > 84.1 (for quantitative) and m/z 219.1 > m/z 130.1 for CEL, and m/z 180.1 > 80.1 for cotinine-D3, respectively. RESULTS: The separation of CML and CEL was accomplished within a total analysis time of 6 minutes. The retention times of CML, CEL, and cotinine-D3 were 3.43 minutes, 3.46 minutes, and 4.50 minutes, respectively. The assay exhibited linearity in the concentration range of 0.025-1.500 µmol/L, with a lower limit of quantification of 0.025 µmol/L for both compounds. The relative standard deviations of intra-day and inter-day were both below 9%, and the relative errors were both within the range of ±4%. The average recoveries were 94.24% for CML and 97.89% for CEL. CONCLUSION: The results indicate that the developed methodology is fast, highly sensitive, highly specific, reproducible, and suitable for the rapid detection of CML and CEL in clinical human plasma samples. The outcomes of the clinical research project on aging underscored the important indicative significance of these two indicators for research on human aging.

Rubisco small subunit (RbCS) is co-opted by potyvirids as the scaffold protein in assembling a complex for viral intercellular movement.

Plant viruses must move through plasmodesmata (PD) to complete their life cycles. For viruses in the Potyviridae family (potyvirids), three viral factors (P3N-PIPO, CI, and CP) and few host proteins are known to participate in this event. Nevertheless, not all the proteins engaging in the cell-to-cell movement of potyvirids have been discovered. Here, we found that HCPro2 encoded by areca palm necrotic ring spot virus (ANRSV) assists viral intercellular movement, which could be functionally complemented by its counterpart HCPro from a potyvirus. Affinity purification and mass spectrometry identified several viral factors (including CI and CP) and host proteins that are physically associated with HCPro2. We demonstrated that HCPro2 interacts with both CI and CP in planta in forming PD-localized complexes during viral infection. Further, we screened HCPro2-associating host proteins, and identified a common host protein in Nicotiana benthamiana-Rubisco small subunit (NbRbCS) that mediates the interactions of HCPro2 with CI or CP, and CI with CP. Knockdown of NbRbCS impairs these interactions, and significantly attenuates the intercellular and systemic movement of ANRSV and three other potyvirids (turnip mosaic virus, pepper veinal mottle virus, and telosma mosaic virus). This study indicates that a nucleus-encoded chloroplast-targeted protein is hijacked by potyvirids as the scaffold protein to assemble a complex to facilitate viral movement across cells.

Visible light-induced C(sp3)-H azolation of ethers via radical-polar crossover.

Reported herein is a photochemical strategy for C(sp3)-H azolation of ethers via a hydrogen-atom transfer and radical-polar crossover process, offering efficient access to valuable N-alkylated azoles under visible-light irradiation. The protocol is metal-free and photocatalyst-free, and exhibits good to excellent yields and broad substrate scope with regard to azoles. EPR experiments provide evidence for the formation of intermediates formed in situ.

Upfront Umbilical Cord Blood Transplantation Versus Immunosuppressive Therapy for Pediatric Patients With Idiopathic Severe Aplastic Anemia.

Umbilical cord blood transplantation (UCBT) has been rarely reported as a first-line treatment for idiopathic severe aplastic anemia (SAA) patients lacking HLA-matched sibling donors (MSD). Our study aimed to compare the clinical outcomes of pediatric SAA patients who received UCBT and immunosuppressive therapy (IST) upfront. A retrospective analysis was performed on 43 consecutive patients who received frontline IST (n = 17) or UCBT (n = 26) between July 2017 and April 2022. The 3-year overall survival (OS) was comparable between the UCBT and IST groups (96.2% versus 100%, P = .419), while the 3-year event-free survival (EFS) was significantly better in the former than in the latter (88.5% versus 58.8%, P = .048). In the UCBT group, 24 patients achieved successful engraftment, 2 patients developed severe acute graft-versus-host disease (aGVHD), no extensive chronic GVHD (cGVHD), and a high GVHD-free, failure-free survival (GFFS) of 84.6% at 3 years. After 1 year of treatment, 12 patients in the IST group responded, while 5 patients did not achieve remission and 2 patients had disease relapse. At both 3 and 6 months after treatment, the proportion of transfusion-independent patients was higher in the UCBT group than in the IST group. Faster immune recovery and earlier transfusion independence further reduced the risk of infection and bleeding, thereby improving health-related quality of life in the UCBT-treated group. Our results suggested that UCBT as upfront therapy may be an effective and safe option for pediatric SAA patients, with favorable outcomes in experienced centers.

An integrated system combining Tetrasphaera-dominated enhanced biological phosphorus removal with sulfur autotrophic denitrification to enhance biological nutrients removal.

This study developed a two-stage process, including Tetrasphaera-dominated enhanced biological phosphorus-removal (EBPR(T)) sequencing batch reactor (SBR), followed by sulfur autotrophic denitrification (SADN) SBR, to achieve advanced nutrients removal from low VFAs wastewater. The removal efficiencies of nitrogen and phosphorus (PO43--P) reached 99 % with effluent PO43--P and total inorganic nitrogen (TIN) below 0.5 mg/L and 1 mg/L in EBPR(T) and SADN SBR, respectively. Mechanism analysis indicated that as increasing drainage ratio and complex carbon sources, free amino acids, glycogen, and PHA served as the endogenous carbon sources of Tetrasphaera to store energy. SADN contributed to approximately 80 % of nitrogen removal. DNA and cDNA results indicated Tetrasphaera was shifted from clade 2 to clade 1 after increasing the drainage ratio and the complexity of the carbon source, and Tetrasphaera (50.95 %) and Ca. Accumulibacter (9.12 %) were the most important functional microorganisms synergized to remove phosphorus at the transcriptional level in EBPR(T). Thiobacillus (45.97 %) and Sulfuritalea (9.24 %) were the dominant sulfur autotrophic denitrifiers at gene and transcriptional level in SADN. The results suggested that the EBPR(T) - SADN SBRs have great nutrient removal performance in treating low VFAs wastewater without additional carbon sources.

Predatory protists reduce bacteria wilt disease incidence in tomato plants.

Soil organisms are affected by the presence of predatory protists. However, it remains poorly understood how predatory protists can affect plant disease incidence and how fertilization regimes can affect these interactions. Here, we characterise the rhizosphere bacteria, fungi and protists over eleven growing seasons of tomato planting under three fertilization regimes, i.e conventional, organic and bioorganic, and with different bacterial wilt disease incidence levels. We find that predatory protists are negatively associated with disease incidence, especially two ciliophoran Colpoda OTUs, and that bioorganic fertilization enhances the abundance of predatory protists. In glasshouse experiments we find that the predatory protist Colpoda influences disease incidence by directly consuming pathogens and indirectly increasing the presence of pathogen-suppressive microorganisms in the soil. Together, we demonstrate that predatory protists reduce bacterial wilt disease incidence in tomato plants via direct and indirect reductions of pathogens. Our study provides insights on the role that predatory protists play in plant disease, which could be used to design more sustainable agricultural practices.

Pain Reduction and Changes in Serum Cortisol, Adrenocorticotropic Hormone, and Glucose Levels after Epidural Injections With Different Doses of Corticosteroid.

BACKGROUND: An epidural steroid injection (ESI) effectively relieves acute lumbar discogenic radicular pain. Corticosteroids, a key ESI component, reduce pain by curbing inflammation and blocking pain signal transmission via C-fibers. While prior research confirms the efficacy of 40 mg and 80 mg methylprednisolone, the effectiveness of lower doses remains uncertain. OBJECTIVES: This trial aimed to compare the pain-relieving effects of ESI using varying methylprednisolone doses (10 mg, 20 mg, and 40 mg). Additionally, it sought to examine changes in fasting plasma glucose (FPG), serum cortisol, and serum adrenocorticotropic hormone (ACTH) levels across these groups. STUDY DESIGN: A prospective observational study. SETTING: Department of Pain Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, People's Republic of China. METHODS: Ninety-three patients underwent a single epidural injection of methylprednisolone at different doses: 10 mg (n = 28), 20 mg (n = 32), and 40 mg (n = 33). We evaluated their Numeric Rating Scale (NRS-11) score and Oswestry Disability Index (ODI) score at preinjection and 7 days postinjection. We also measured FPG, serum cortisol, and ACTH levels at baseline and one day postinjection. RESULTS: Significant differences were observed in the likelihood of achieving substantial pain relief among the 3 groups at 7 days postinjection. Specifically, 10 mg vs 20 mg had an odds ratio (OR) of 6.546 (95% CI, 1.161 - 26.513, P = 0.008), and 10 mg vs 40 mg had an OR of 7.753 (95% CI, 1.98 - 30.353, P = 0.003). However, there was no significant difference between 40 mg and 20 mg, with an OR of 0.844 (95% CI, 0.239 - 2.987, P = 0.793) in Model 3. Additionally, the baseline NRS-11 score significantly predicted substantial pain relief, with an OR of 0.47 (95% CI, 0.287 - 0.768, P = 0.003). Furthermore, at 7 days postinjection, the ODI score was significantly lower in the 20 mg group (P = 0.007) and the 40 mg group (P < 0.001) compared to the 10 mg group. Moreover, the difference in serum cortisol and FPG between the 40 mg and 10 mg groups was more pronounced (P < 0.01), while the difference in ACTH was similar among all 3 groups (P = 0.191). LIMITATIONS: Potential selection bias and a short follow-up period may have influenced our study, and certain imaging results were omitted from the regression models. CONCLUSIONS: The effectiveness of ESI in relieving pain was found to be similar for both 20 mg and 40 mg doses, but with fewer changes in FPG and serum cortisol levels for the former (which were not statistically significant). As a result, it may be clinically viable to use a 20 mg dose for achieving short-term pain relief. Moreover, the baseline NRS-11 scores were found to be a reliable predictor of pain relief efficacy, with milder baseline pain intensity being associated with better pain relief outcomes.

Combined Phototrophic Simultaneous Nitrification-Endogenous Denitrification with Phosphorus Removal (P-SNDPR) System Treating Low Carbon to Nitrogen Ratio Wastewater for Potential Carbon Neutrality.

Conventional biological nutrient removal processes rely on external aeration and produce significant carbon dioxide (CO2) emissions. This study constructed a phototrophic simultaneous nitrification-denitrification phosphorus removal (P-SNDPR) system to treat low carbon to nitrogen (C/N) ratios wastewater and investigated the impact of sludge retention time (SRT) on nutrient removal performance, nitrogen conversion pathway, and microbial structure. Results showed that the P-SNDPR system at SRT of 15 days had the highest nutrient removal capacity, achieving over 85% and 98% removal of nitrogen and phosphorus, respectively, meanwhile maintaining minimal CO2 emissions. Nitrogen removal was mainly through assimilation at SRTs of 5 and 10 days, and nitrification-denitrification at SRTs of 15 and 20 days. Stable partial nitrification was facilitated by photoinhibition and low DO levels. Flow cytometry sorting technique results revealed SRT drove community structural changes in translational activity (BONCAT+) microbes, where BONCAT+ microbes were mainly simultaneous nitrogen and phosphorus removal bacteria (Candidatus Accumulibacter), denitrifying bacteria (Candidatus Competibacter and Plasticicumulans), ammonia-oxidizing bacteria (Nitrosomonas), and microalgae (Chlorella and Dictyosphaerium). The P-SNDPR system represents a novel, carbon-neutral process for efficient nutrient removal from low C/N ratio wastewater without aeration and external carbon source additions.

Efficacy of bortezomib, cyclophosphamide, and dexamethasone for newly diagnosed POEMS syndrome patients.

Background: Due to the rarity of polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome, the best first-line treatment has not been established, although there are several options in guidelines. The preferred treatments vary according to the preference of the physician and anecdote. Objectives: First, to analyze the efficacy of a new treatment mode in POEMS syndrome that uses the four-cycle treatment as the induction regimen, followed by sequential transplantation as the consolidation regimen for transplantation-eligible patients, or received another two-cycle treatment for transplantation-ineligible patients. Second, to compare the efficacy and safety of regimens with a proteasome inhibitor (bortezomib-cyclophosphamide-dexamethasone, BCD) or without a proteasome inhibitor (cyclophosphamide-dexamethasone ± thalidomide, CD ± T). Design: We conducted a retrospective study using real-world data from Capital Medical University, Xuanwu Hospital. Methods: A total of 34 newly diagnosed POEMS syndrome patients met Dispenzieri's diagnostic criteria, and those who completed at least four cycles of treatment from July 2013 to March 2021 were included. Results: The overall vascular endothelial growth factor (VEGF) response rate of this new treatment mode was 100%. The cumulative VEGF complete remission (CRV) rate was 67.9%, and the cumulative complete hematological response (CRH) rate was 55.6%. During the median 49-month follow-up, the 5-year-overall survival (OS) rate was 90.7%, the 3-year-progression-free survival (PFS) rate was 78.4%, and the 5-year-PFS rate was 73.8%. The BCD regimen achieved a 75% CRV rate (median time from diagnosis to CRV = 130 days) and 66.7% CRH rate (median time from diagnosis to CRH = 218 days). In addition, the VEGF response was less than the partial remission (PRV) after four-cycle induction treatment, which, together with a decrease on the Overall Neurological Limitation Scale of less than three points 1 year after consolidation treatment, was an independent poor prognostic factor. Conclusion: Bortezomib was well-tolerated by patients with POEMS syndrome. Compared with CD ± T regimen, BCD as the induction regimen achieved better VEGF response and earlier hematological remission. Autologous stem cell transplantation used as consolidation therapy further improved the neurological and hematological remission rates, resulting in better OS and PFS.

Anatomical Study of Cross-Transfer of the Contralateral C7 Nerve Through the Posterior Epidural Pathway of the Cervical Spine for the Treatment of Spastic Paralysis of the Upper Limbs.

BACKGROUND: This study explored the safety and feasibility of surgical treatment of spastic paralysis of the central upper extremity by contralateral cervical 7 nerve transfer via the posterior epidural pathway of the cervical spine. METHODS: Five fresh head and neck anatomical specimens were employed to simulate contralateral cervical 7 nerve transfer through the posterior epidural pathway of the cervical spine. The relevant anatomical landmarks and surrounding anatomical relationships were observed under a microscope, and the relevant anatomical data were measured and analysed. RESULTS: The posterior cervical incision revealed the cervical 6 and 7 laminae, and lateral exploration revealed the cervical 7 nerve. The length of the cervical 7 nerve outside the intervertebral foramen was measured to be 6.4 ± 0.5 cm. The cervical 6 and cervical 7 laminae were opened with a milling cutter. The cervical 7 nerve was extracted from the inner mouth of the intervertebral foramen, and its length was 7.8 ± 0.3 cm. The shortest distance of the cervical 7 nerve transfer via the posterior epidural pathway of the cervical spine was 3.3 ± 0.3 cm. CONCLUSIONS: Cross-transfer surgery of the contralateral cervical 7 nerve via the posterior epidural pathway of the cervical spine can effectively avoid the risk of nerve and blood vessel damage in anterior cervical nerve 7 transfer surgery; the nerve transfer distance is short, and nerve transplantation is not required. This approach may become a safe and effective procedure for the treatment of central upper limb spastic paralysis.

Dynamic Monkey Bar Mechanism of Superionic Li-ion Transport in LiTaCl6.

The LiTaCl6 solid electrolyte has the lowest activation energy of ionic conduction at ambient conditions (0.165 eV), with a record high ionic conductivity for a ternary compound (11 mS cm-1 ). However, the mechanism has been unclear. We train machine-learning force fields (MLFF) on ab initio molecular dynamics (AIMD) data on-the-fly and perform MLFF MD simulations of AIMD quality up to the nanosecond scale at the experimental temperatures, which allows us to predict accurate activation energy for Li-ion diffusion (at 0.164 eV). Detailed analyses of trajectories and vibrational density of states show that the large-amplitude vibrations of Cl- ions in TaCl6 - enable the fast Li-ion transport by allowing dynamic breaking and reforming of Li-Cl bonds across the space in between the TaCl6 - octahedra. We term this process the dynamic-monkey-bar mechanism of superionic Li+ transport which could aid the development of new solid electrolytes for all-solid-state lithium batteries.

Preoperative albumin-alkaline phosphatase ratio affects the prognosis of patients undergoing hepatocellular carcinoma surgery.

BACKGROUND: The correlation between the preoperative albuminalkaline phosphatase ratio (AAPR) and the prognosis of hepatocellular carcinoma (HCC) patients after radical resection is still not comprehensive. OBJECTIVE: This study aims to observe the correlation between preoperative AAPR and the prognosis of HCC patients after radical resection. METHODS: We constructed a retrospective cohort study and included 656 HCC patients who underwent radical resection. The patients were grouped after determining an optimum AAPR cut-off value. We used the Cox proportional regression model to assess the correlation between preoperative AAPR and the prognosis of HCC patients after radical resection. RESULTS: The optimal cut-off value of AAPR for assessing the prognosis of HCC patients after radical resection was 0.52 which was acquired by using X-tile software. Kaplan-Meier analysis curves showed that a low AAPR (⩽ 0.52) had a significantly lower rate of overall survival (OS) and recurrence-free survival (RFS) (P< 0.05). Multiple Cox proportional regression showed that an AAPR > 0.52 was a protective factor for OS (HR = 0.66, 95%CI 0.45-0.97, p= 0.036) and RFS (HR = 0.70, 95% CI 0.53-0.92, p= 0.011). CONCLUSIONS: The preoperative AAPR level was related to the prognosis of HCC patients after radical resection and can be used as a routine preoperative test, which is important for early detection of high-risk patients and taking personalized adjuvant treatment.