Design, Synthesis, and Biological Evaluation of Novel Tetrahydroacridin Hybrids with Sulfur-Inserted Linkers as Potential Multitarget Agents for Alzheimer's Disease.

Alzheimer's disease (AD) is a complex neurodegenerative disease that can lead to the loss of cognitive function. The progression of AD is regulated by multiple signaling pathways and their associated targets. Therefore, multitarget strategies theoretically have greater potential for treating AD. In this work, a series of new hybrids were designed and synthesized by the hybridization of tacrine (4, AChE: IC50 = 0.223 µM) with pyrimidone compound 5 (GSK-3ß: IC50 = 3 µM) using the cysteamine or cystamine group as the connector. The biological evaluation results demonstrated that most of the compounds exhibited moderate to good inhibitory activities against acetylcholinesterase (AChE) and glycogen synthase kinase 3ß (GSK-3ß). The optimal compound 18a possessed potent dual AChE/GSK-3ß inhibition (AChE: IC50 = 0.047 ± 0.002 µM, GSK-3ß: IC50 = 0.930 ± 0.080 µM). Further molecular docking and enzymatic kinetic studies revealed that this compound could occupy both the catalytic anionic site and the peripheral anionic site of AChE. The results also showed a lack of toxicity to SH-SY5Y neuroblastoma cells at concentrations of up to 25 µM. Collectively, this work explored the structure-activity relationships of novel tetrahydroacridin hybrids with sulfur-inserted linkers, providing a reference for the further research and development of new multitarget anti-AD drugs.

Relationship Between Climate Change and Marmot Plague of Marmota himalayana Plague Focus - the Altun Mountains of the Qinghai-Xizang Plateau, China, 2000-2022.

Introduction: Plague is a zoonotic disease that occurs naturally in specific geographic areas. Climate change can influence the populations of the plague host or vector, leading to variations in the occurrence and epidemiology of plague in animals. Methods: In this study, we collected meteorological and plague epidemiological data from the Marmota himalayana plague focus in the Altun Mountains of the Qinghai-Xizang Plateau. The data spanned from 2000 to 2022. We describe the climatic factors and plague epidemic conditions and we describe their analysis by Pearson's correlation. Results: During the period from 2000 to 2022, the isolation rates of Yersinia pestis (Y.pestis) from marmots and fleas were 9.27% (451/4,864) and 7.17% (118/1,646), respectively. Additionally, we observed a positive rate of F1 antibody of 11.25% (443/3,937) in marmots and 18.16% (142/782) in dogs. With regards to climate, there was little variation, and a decreasing trend in blowing-sand days was observed. The temperature in the previous year showed a negative correlation with the Y. pestis isolation rate in marmots (r=-0.555, P=0.011) and the positive rate of F1 antibody in marmots (r=-0.552, P=0.012) in the current year. The average annual precipitation in the previous two years showed a positive correlation with marmot density (r=0.514, P=0.024), while blowing-sand days showed a negative correlation with marmot density (r=-0.701, P=0.001). Furthermore, the average annual precipitation in the previous three years showed a positive correlation with the isolation rate of Y. pestis from marmots (r=0.666, P=0.003), and blowing-sand days showed a negative correlation with marmot density (r=-0.597, P=0.009). Conclusions: The findings of this study indicate that there is a hysteresis effect of climate change on the prevalence of plague. Therefore, monitoring climate conditions can offer significant insights for implementing timely preventive and control measures to combat plague epidemics.

Pasteurella multocida strains of a novel capsular serotype and lethal to Marmota himalayana on Qinghai-Tibet plateau in China.

Pasteurella multocida is a zoonotic pathogen causing serious diseases in humans and animals. Here, we report P. multocida from wildlife on China's Qinghai-Tibet plateau with a novel capsular serotype, forming a single branch on the core-genome phylogenetic tree: four strains isolated from dead Himalayan marmot (Marmota himalayana) and one genome assembled from metagenomic sequencing of a dead Woolly hare (Lepus oiostolus). Four of the strains were identified as subspecies multocida and one was septica. The mouse model showed that the challenge strain killed mice within 24 h at an infectious dose of less than 300 bacteria. The short disease course is comparable to septicemic plague: the host has died before more severe pathological changes could take place. Though pathological changes were relatively mild, cytokine storm was obvious with a significant rise of IL-12p70, IL-6, TNF-αand IL-10 (P < 0.05). Our findings suggested P. multocida is a lethal pathogen for wildlife on Qinghai-Tibet plateau, in addition to Yersinia pestis. Individuals residing within the M. himalayana plague focus are at risk for P. multocida infection, and public health warnings are necessitated.

Efficacy and safety of apatinib plus chemotherapy vs. chemotherapy alone for the treatment of advanced­stage non­small cell lung cancer: A meta­analysis.

Apatinib has been widely applied for the treatment of gastrointestinal cancer since its development; however, available conclusive data regarding its use in non-small cell lung cancer (NSCLC) are lacking. Thus, the present meta-analysis aimed to compare the efficacy and safety of the use of apatinib plus chemotherapy vs. chemotherapy alone for the treatment of patients with advanced-stage NSCLC. Published studies reporting the treatment response, progression-free survival (PFS), overall survival (OS) and adverse events in patients with advanced-stage NSCLC treated with apatinib plus chemotherapy or chemotherapy alone were searched using the PubMed, China National Knowledge Infrastructure, EMBASE, Chongqing VIP Information, Cochrane and Wanfang databases until February 2023. Finally, 18 studies involving 677 patients with NSCLC receiving apatinib plus chemotherapy and 672 patients with NSCLC receiving chemotherapy were included in the present analysis. Apatinib plus chemotherapy was found to increase the objective response rate [relative risk (RR), 1.60; 95% confidence interval (CI), 1.38-1.86] and disease control rate (RR, 1.29; 95% CI, 1.21-1.38) compared to chemotherapy alone. Of note, apatinib plus chemotherapy also prolonged PFS compared with chemotherapy alone (hazard ratio, 0.54; 95% CI, 0.35-0.73), while no OS data were retrievable from the included studies. With regard to safety, apatinib plus chemotherapy elevated the risk of developing hypertension (RR, 3.78; 95% CI, 1.81-7.93) and hand-foot syndrome (RR, 6.51; 95% CI, 3.70-11.46) vs. chemotherapy alone; however, no difference was observed between the two regimens in terms of the incidence of other adverse events. Furthermore, the bias was low and the pooled findings were reliable/stable, as indicated by a sensitivity analysis. On the whole, the present study demonstrates that apatinib plus chemotherapy increases the treatment response and PFS vs. chemotherapy alone, while it also elevates the risk of developing hypertension and hand-foot syndrome in patients with advanced-stage NSCLC.

Case report: A case of brucellosis misdiagnosed as coronavirus disease 2019/influenza in China.

Brucellosis is an important zoonosis and a multisystem disease. The signs and symptoms of brucellosis are not specific. In the clinical, brucellosis is often ignored and misdiagnosed. We report a case of brucellosis who was misdiagnosed as coronavirus disease 2019 (COVID-19)/influenza and received delayed treatment during strict COVID-19 control. The neglect of other diseases due to COVID-19 and empirical diagnosis and treatment by medical staff are part of the reasons for misdiagnosis. Otherwise, the normal erythrocyte sedimentation rate (ESR), increased white blood cell count (WBC), and increased neutrophil count (NEUT) of this patient was also a cause of misdiagnosis, which is an important reminder for diagnosis. For patients with the unknown origin of fever and other symptoms related to brucellosis, especially those from endemic areas of brucellosis, brucellosis screening is a priority item, and grassroots doctors should be vigilant and standardize the diagnosis and treatment based on epidemiology history, clinical manifestation, and laboratory tests according to the diagnostic criteria of brucellosis.

The complex genomic diversity of Yersinia pestis on the long-term plague foci in Qinghai-Tibet plateau.

Plague is a typical natural focus disease that circulates in different ecology of vectors and reservoir hosts. We conducted genomic population and phylogenetic analyses of the Yersinia pestis collected from the 12 natural plague foci in China with more than 20 kinds of hosts and vectors. Different ecological landscapes with specific hosts, vectors, and habitat which shape various niches for Y. pestis. The phylogeographic diversity of Y. pestis in different kinds plague foci in China showed host niches adaptation. Most natural plague foci strains are region-and focus-specific, with one predominant subpopulation; but the isolates from the Qinghai-Tibet plateau harbor a higher genetic diversity than other foci. The Y. pestis from Marmota himalayana plague foci are defined as the ancestors of different populations at the root of the evolutionary tree, suggesting several different evolutionary paths to other foci. It has the largest pan-genome and widest SNP distances with most accessory genes enriched in mobilome functions (prophages, transposons). Geological barriers play an important role in the maintenance of local Y. pestis species and block the introduction of non-native strains. This study provides new insights into the control of plague outbreaks and epidemics, deepened the understanding of the evolutionary history of MHPF (M. himalayana plague focus) in China. The population structure and identify clades among different natural foci of China renewed the space cognition of the plague.

Efficient NH3-Tolerant Nickel-Based Hydrogen Oxidation Catalyst for Anion Exchange Membrane Fuel Cells.

Converting hydrogen chemical energy into electrical energy by fuel cells offers high efficiencies and environmental advantages, but ultrapure hydrogen (over 99.97%) is required; otherwise, the electrode catalysts, typically platinum on carbon (Pt/C), will be poisoned by impurity gases such as ammonia (NH3). Here we demonstrate remarkable NH3 resistivity over a nickel-molybdenum alloy (MoNi4) modulated by chromium (Cr) dopants. The resultant Cr-MoNi4 exhibits high activity toward alkaline hydrogen oxidation and can undergo 10,000 cycles without apparent activity decay in the presence of 2 ppm of NH3. Furthermore, a fuel cell assembled with this catalyst retains 95% of the initial peak power density even when NH3 (10 ppm)/H2 was fed, whereas the power output reduces to 61% of the initial value for the Pt/C catalyst. Experimental and theoretical studies reveal that the Cr modifier not only creates electron-rich states that restrain lone-pair electron donation but also downshifts the d-band center to suppress d-electron back-donation, synergistically weakening NH3 adsorption.

Rare case of bacteremia due to Lysinibacillus sphaericus in a person living with HIV.

Lysinibacillus sphaericus, as an insect pathogen, is a ubiquitous Gram-positive bacterium present in the environment. It is often considered to be contaminating bacteria. L. sphaericus has been reported to cause infectious diseases in humans relatively rarely. We report a rare case of bacteremia due to L. sphaericus in a person living with HIV, which is also the first reported case of bacteremia caused by L. sphaericus in China. L. sphaericus easily causes infection in immunocompromised individuals. We found that L. sphaericus and Lysinibacillus fusiformis could not be distinguished by their 16S ribosomal RNA gene sequence. We performed a genome-wide analysis of the isolated strains of this case and predicted the virulence factors. Finally, L. sphaericus was confirmed. According to antimicrobial susceptibility test, the strain was found to be sensitive to levofloxacin and vancomycin but resistant to penicillin. Greater attention to L. sphaericus infection should be paid and immunocompromised populations should be protected from L. sphaericus infection.

Preparation and Bioevaluation of 18F-Labeled Small-Molecular Radiotracers via Sulfur(VI) Fluoride Exchange Chemistry for Imaging of Programmed Cell Death Protein Ligand 1 Expression in Tumors.

Nowadays, one of the most effective methods of tumor immunotherapy is blocking programmed cell death protein 1/programmed cell death protein ligand 1 (PD-1/PD-L1) immune checkpoints. However, there is still a significant challenge in selecting patients to benefit from immune checkpoint therapies. Positron emission tomography (PET), a noninvasive molecular imaging technique, offers a new approach to accurately detect PD-L1 expression and allows for a better prediction of response to PD-1/PD-L1 target immunotherapy. Here, we designed and synthesized a novel group of aryl fluorosulfate-containing small-molecule compounds (LGSu-1, LGSu-2, LGSu-3, and LGSu-4) based on the phenoxymethyl-biphenyl scaffold. After screening by the time-resolved fluorescence resonance energy transfer (TR-FRET) assay, the most potent compound LGSu-1 (half maximal inhibitory concentration (IC50): 15.53 nM) and the low-affinity compound LGSu-2 (IC50: 189.70 nM) as a control were selected for 18F-radiolabeling by sulfur(VI) fluoride exchange chemistry (SuFEx) to use for PET imaging. [18F]LGSu-1 and [18F]LGSu-2 were prepared by a one-step radiofluorination reaction in over 85% radioconversion and nearly 30% radiochemical yield. In B16-F10 melanoma cell assays, [18F]LGSu-1 (5.00 ± 0.06%AD) showed higher cellular uptake than [18F]LGSu-2 (2.55 ± 0.04%AD), in which cell uptake could be significantly blocked by the nonradioactivity LGSu-1. In vivo experiments, micro-PET imaging of B16-F10 tumor-bearing mice and radiographic autoradiography of tumor sections showed that [18F]LGSu-1 was more effectively accumulated in the tumor due to the higher binding affinity with PD-L1. The above experimental results confirmed the potential of the small-molecule probe LGSu-1 as a targeting PD-L1 imaging tracer in tumor tissues.

Promising therapeutic mechanism for Chinese herbal medicine in ameliorating renal fibrosis in diabetic nephropathy.

Diabetic nephropathy (DN) is one of the most serious chronic microvascular abnormalities of diabetes mellitus and the major cause of uremia. Accumulating evidence has confirmed that fibrosis is a significant pathological feature that contributes to the development of chronic kidney disease in DN. However, the exact mechanism of renal fibrosis in DN is still unclear, which greatly hinders the treatment of DN. Chinese herbal medicine (CHM) has shown efficacy and safety in ameliorating inflammation and albuminuria in diabetic patients. In this review, we outline the underlying mechanisms of renal fibrosis in DN, including oxidative stress (OS) generation and OS-elicited ASK1-p38/JNK activation. Also, we briefly summarize the current status of CHM treating DN by improving renal fibrosis. The treatment of DN by inhibiting ASK1 activation to alleviate renal fibrosis in DN with CHM will promote the discovery of novel therapeutic targets for DN and provide a beneficial therapeutic method for DN.

Persistent Urinary Tract Infection in Association with Community-Acquired NDM-5 Escherichia coli Clonal Group Following COVID-19 Infection - Beijing Municipality, China, 2023.

What is already known about this topic?: The hospital-acquired infections caused by New Delhi metallo-beta-lactamase (NDM)-producing strains are typically attributed to a single clonal lineage. What is added by this report?: In this study, we encountered a unique case of community-acquired NDM-5 Escherichia coli urinary tract infection (UTI) following coronavirus disease 2019 (COVID-19). The UTI persisted for a duration of at least 45 days. Genomic analyses revealed the presence of two NDM-5 strains, both sharing an identical chromosomal background but distinct, homologous, and recombined plasmids. This case suggests that a diverse range of resistance genes may be present within the human body, with drug-resistant strains undergoing continuous evolution during infection. The intestinal tract may have been its drug-resistant gene pool. What are the implications for public health practice?: The observations presented in this case indicate that the endogenous acquisition of drug-resistant genes may also be an issue in managing multidrug-resistant organisms (MDRO). It is possible for continuous recombination to occur within carbapenem-resistant Enterobacteriaceae (CRE) during infection. In contrast to exogenously-acquired resistance, greater attention should be placed on the endogenous factors that contribute to the development of CRE within healthcare settings.

Identification of Novel Bartonella washoensis Sequence Type 22 in Marmota himalayana - Jiuquan City, Gansu Province, China, 2021-2022.

What is already known about this topic?: The prevalence of rodent-adapted Bartonella species has been increasing significantly. However, the specific Bartonella species carried by Marmota himalayana (M. himalayana), a large rodent species, and the potential risk it poses to human populations remain unknown. What is added by this report?: Bartonella washoensis (B. washoensis), associated with human endocarditis, was initially identified in M. himalayana, exhibiting a detection rate of approximately one-third and demonstrating a predilection for the heart and lungs. The discovery of the novel Sequence Type 22 has expanded both the isolation source and genetic lineage of B. washoensis. What are the implications for public health practice?: Individuals residing within the M. himalayana plague focus are at an elevated risk for B. washoensis infection. Consequently, there is a pressing need for public health warnings and efficient clinical case identification in this population.

Case Report: Screening and Analysis for Brucellosis in Akesai Kazak Autonomous County, China.

Brucellosis is a common zoonotic disease. For this study, the residents of Akesai Kazak Autonomous County, located in the high altitude of the Altun Mountains region of Gansu Province, were selected. These people rely on traditional animal husbandry for their main income. The prevalence of brucellosis and the change of antibody titer in this high-risk population were analyzed, and information on the epidemic in animals in the county was obtained from data records. One hundred ninety-nine persons were screened and 240 serum samples were collected. Eight persons and 27 serum samples were positive based on the rose bengal plate test, and seven persons were confirmed positive by standard agglutination test; 16,000 sheep were tested, of which 130 from nine different households were serum antibody positive. The results indicate that brucellosis seroprevalence increased among sheep and high-risk populations, and the occurrence of cases corresponded to the epidemic among animals. The incidence of human brucellosis was closely related to occupation, and the cases were mainly distributed among herdsmen and butchers. Most cases were asymptomatic or mild, and the serum antibody titers showed a high initial titer but a rapid decline in young cases, whereas those in older cases were relatively low but showed a slow decline.

Palladium single-atom catalysts synthesized by a gas-assisted redispersion strategy for efficient benzaldehyde hydrogenation.

A simple and efficient strategy was developed for the synthesis of Pd single-atom catalysts (PdSA/G) by nitric acid vapor-assisted redispersion. The as-prepared PdSA/G displayed robust catalytic performance in the selective hydrogenation reaction of benzaldehyde. This work paves a new way for the design of supported Pd single-atom catalysts.

Development of a multifunctional platform for near-infrared imaging and targeted radionuclide therapy for tumors.

Biotin receptor (BR) is overexpressed in several human tumor cell lines and has become an important biomarker for tumor diagnosis and treatment. Therefore, much attention has been attracted in the field of developing BR-targeting agents. In clinical practice, a multifunctional platform that can be used for both diagnosis and treatment is much desirable. In this study, to improve diagnostic and therapeutic efficacy of BR-positive tumors, we developed a multifunctional platform RT-H2 to combine with the cyanine scaffold for near infrared (NIR) imaging and the radioisotope 131I for targeted radionuclide therapy (TRT). In vitro experiments showed that RT-H2 possessed favorable NIR properties and could selectively accumulate in BR-positive HeLa cells. In vivo NIR imaging of HeLa tumor-bearing mice exhibited high accumulation and long retention time (72 h) of RT-H2 in the tumor. Furthermore, RT-H2 was also employed as a carrier to develop 131I-labeled TRT agent due to its favorable properties in vivo. The radiolabeling conditions were optimized and the optimal conditions determined to be 1.2 equiv of Idogen, reaction time 4 min and room temperature, yielding the radiotracer [131I]I-RT-H2 with the radiochemical purity (RCP) of > 95% after a simple purification by a C18 column. In vitro cell experiments indicated that [131I]I-RT-H2 could specifically target Hela cells and displayed dose-dependent antitumor effect. In vivo experiments demonstrated that [131I]I-RT-H2 obviously inhibited the tumor proliferation in HeLa tumor-bearing mice within 4 weeks. All these results indicate that RT-H2 has the potential to serve as a multifunctional platform for tumor diagnosis and treatment.

Emission reduction of PCDD/Fs by flue gas recirculation and activated carbon in the iron ore sintering.

One of the main sources of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) in the environment is the sintering of iron ore. Both flue gas recirculation (FGR) and activated carbon (AC), which have the impact of decreasing both PCDD/Fs and conventional pollutants (NOx, SO2, etc.), are significant technologies for the abatement of PCDD/Fs from the sintering exhaust gas. This work involved the first measurement of PCDD/Fs emissions during FGR and a thorough analysis of the impact of PCDD/Fs reduction following the coupling of FGR and AC technologies. According to the measured data, the ratio of PCDFs to PCDDs in the sintered flue gas was 6.8, indicating that during the sintering process, the PCDD/Fs were primarily produced by de novo synthesis. Further investigation revealed that FGR initially removed 60.7% of PCDD/Fs by returning it to the high temperature bed, and AC further removed 95.2% of the remaining PCDD/Fs through physical adsorption. While AC is better at removing PCDFs and can efficiently remove tetra-to octa-chlorinated homologs, FGR is more effective at removing PCDDs and has higher removal efficiency for hexa-to octa-chlorinated PCDD/Fs. Together, they complement each other with a removal rate of 98.1%. The study's findings are instructional for the process design of combining FGR and AC technologies to reduce PCDD/Fs in the sintered flue gas.

Neuropilin 1-targeted near-infrared fluorescence probes for tumor diagnosis.

Two neuropilin 1 (NRP1)-targeted near-infrared fluorescence probes for tumor imaging were synthesized via click reaction. These two probes achieve excellent solubility and less aggregation. Importantly, they were able to rapidly target NRP1-overexpressing tumors and had long retention within tumors. Additionally, QS-1 with appropriate hydrophilicity displays higher tumor to muscle (T/M) ratio. And QS-1 can be easily modified with other functional group, and serve as a platform for constructing dual-modal or dual-targeting probes.

Interfacial Engineering of Ni/V2 O3 Heterostructure Catalyst for Boosting Hydrogen Oxidation Reaction in Alkaline Electrolytes.

Alkaline fuel cells can permit the adoption of platinum group metal-free (PGM-free) catalysts and cheap bipolar plates, thus further lowering the cost. With the exploration of PGM-free hydrogen oxidation reaction (HOR) catalysts, nickel-based compounds have been considered as the most promising HOR catalysts in alkali. Here we report an interfacial engineering through the formation of nickel-vanadium oxide (Ni/V2 O3 ) heterostructures to activate Ni for efficient HOR catalysis in alkali. The strong electron transfer from Ni to V2 O3 could modulate the electronic structure of Ni sites. The optimal Ni/V2 O3 catalyst exhibits a high intrinsic activity of 0.038 mA cm-2 and outstanding stability. Experimental and theoretical studies reveal that Ni/V2 O3 interface as the active sites can enable to optimize the hydrogen and hydroxyl bindings, as well as protect metallic Ni from extensive oxidation, thus achieving the notable activity and durability.

Serological investigation of plague and brucellosis infection in Marmota himalayana plague foci in the Altun Mountains on the Qinghai-Tibet Plateau.

The Altun Mountains are among the most active regions of Marmota himalayana plague foci of the Qinghai-Tibet Plateau where animal plague is prevalent, whereas only three human cases have been found since 1960. Animal husbandry is the main income for the local economy; brucellosis appears sometimes in animals and less often in humans. In this study, a retrospective investigation of plague and brucellosis seroprevalence among humans and animals was conducted to improve prevention and control measures for the two diseases. Animal and human sera were collected for routine surveillance from 2018 to 2021 and screened for plague and brucellosis. Yersinia pestis F1 antibody was preliminarily screened by the colloidal gold method at the monitoring site to identify previous infections with positive serology. Previous plague infection was found in 3.2% (14/432) of the studied human population having close contact with livestock, which indicates evidence of exposure to the Yersinia antigen (dead or live pathogenic materials) in the Altun Mountains. Seroprevalence of brucellosis was higher in camels (6.2%) and sheepdogs (1.8%) than in other livestock such as cattle and sheep, suggesting a possible transmission route from secondary host animals to humans.

Band-tunable achromatic metalens based on phase change material.

Achromatic metalens have the potential to significantly reduce the size and complexity of broadband imaging systems. A large variety of achromatic metalens has been proposed and most of them have the fixed achromatic band that cannot be actively modified. However, band-tunable is an important function in practical applications such as fluorescence microscopic imaging and optical detection. Here, we propose a bilayer metalens that can switch achromatic bands by taking the advantage of the high refractive index contrast of Sb2S3 between amorphous and crystalline state. By switching the state of Sb2S3, the achromatic band can be reversibly switched between the red region of visible spectrum (650-830 nm) and the near-infrared spectrum (830-1100 nm). This band-tunable design indicates a novel (to our knowledge) method to solve the problem of achromatic focusing in an ultrabroad band. The metalens have an average focusing efficiency of over 35% and 55% in two bands while maintaining diffraction-limited performance. Moreover, through proper design, we can combine different functionalities in two bands such as combining achromatic focusing and diffractive focusing. The proposed metalens have numerous potential applications in tunable displaying, detecting devices and multifunctional devices.