Molecular Engineering of AIE Photosensitizers for Inactivation of Rabies Virus.

Rabies is a zoonotic neurological disease caused by the rabies virus (RABV) that is fatal to humans and animals. While several post-infection treatment have been suggested, developing more efficient and innovative antiviral methods are necessary due to the limitations of current therapeutic approaches. To address this challenge, a strategy combining photodynamic therapy and immunotherapy, using a photosensitizer (TPA-Py-PhMe) with high type I and type II reactive oxygen species (ROS) generation ability is proposed. This approach can inactivate the RABV by killing the virus directly and activating the immune response. At the cellular level, TPA-Py-PhMe can reduce the virus titer under preinfection prophylaxis and postinfection treatment, with its antiviral effect mainly dependent on ROS and pro-inflammatory factors. Intriguingly, when mice are injected with TPA-Py-PhMe and exposed to white light irradiation at three days post-infection, the onset of disease is delayed, and survival rates improved to some extent. Overall, this study shows that photodynamic therapy and immunotherapy open new avenues for future antiviral research.

A highly sensitive and selective detection of 2,4,6-trinitrotoluene (TNT) using a peptide-functionalized silicon nanowire array sensor.

A highly sensitive and specific detection of 2,4,6-trinitrotoluene (TNT), a typical nitrated aromatic explosive, was demonstrated by a silicon nanowire (SiNW) array sensor. The SiNW array devices were self-assembled and functionalized with the anti-TNT peptide to obtain unique sensitivity toward TNT. Also, the effect of the biointerfacing linker's chemistry and Debye screening with varied ionic strength of phosphate buffer solution (PBS) on TNT binding response signals were investigated. The optimization of the peptide-functionalized SiNW array sensor showed high sensitivity for TNT with a detection limit of 0.2 fM, the highest sensitivity reported to date. These initial promising results may help accelerate the development of portable sensors for femtomolar level TNT detection.

Distinct lake sedimentary imprints of earthquakes, floods and human activities in the Xiaojiang Fault zone: Towards a quantitative paleoseismograph in the southeastern Tibetan Plateau.

Lake sediments that widely distributed in the active and complicated fault zones have been recently showing great potential for paleoseismic reconstruction. However, flood events and human activities may make the seismic signal unrecognizable. In this study, high-resolution analyses of sedimentary structure, physical and chemical proxies, as well as absolutely radioactive dating were conducted on seven representative sediment cores from the depocenter, nearshore and inlet areas of Yangzong Lake, a typical fault lake in the Xiaojiang Fault zone, southeastern Tibetan Plateau (TP). These new data were calibrated by historical documents, suggesting that seismically induced mass-transport deposits (MTDs, i.e., turbidites) were massive and/or amalgamated (earthquake doublet), became fining and thickening towards the lake center (without changing lake morphology), and occasionally exhibited soft sediment deformation structures (SSDs, i.e., microfaults). These sediments were relatively poorly sorted and instantaneously deposited from slope failures within the lake. An extremely strong earthquake could cause coseismic subsidence of the lake basin and destruct the local hydrological system, resulting in exceptionally high Mn and total inorganic carbon (TIC) contents in the lake center. In contrast, flood deposits were thinner with horizontal beddings, had higher terrestrial organic matter (higher C/N ratios), and distributed locally in the lake inlet area. Human activities-induced sediments were inversely graded, poorly sorted and gradually deposited, had horizontal beddings and no erosive base, and exhibited high carbon, Pb and Zn contents and low C/N ratios. In addition, macroseismic investigations and statistical results from intensity prediction equations (IPEs) provided a conservative threshold of ∼8 Modified Mercalli Intensities (MMI) for triggering turbidites, and a ∼ 10 MMI for inducing coseismic subsidence and hydrological destruction. This study was among the first attempts to establish a quantitative lacustrine paleoseismograph in the southeastern TP, and the new results would greatly improve the valid assessment of geohazard risks.

Regulation of innate immune responses by rabies virus.

Rabies virus (RABV) is an infectious and neurotropic pathogen that causes rabies and infects humans and almost all warm-blooded animals, posing a great threat to people and public safety. It is well known that innate immunity is the critical first line of host defense against viral infection. It monitors the invading pathogens by recognizing the pathogen-associated molecular patterns and danger-associated molecular patterns through pattern-recognition receptors, leading to the production of type I interferons (IFNα/ß), inflammatory cytokines, and chemokines, or the activation of autophagy or apoptosis to inhibit virus replication. In the case of RABV, the innate immune response is usually triggered when the skin or muscle is bitten or scratched. However, RABV has evolved many ways to escape or even hijack innate immune response to complete its own replication and eventually invades the central nervous system (CNS). Once RABV reaches the CNS, it cannot be wiped out by the immune system or any drugs. Therefore, a better understanding of the interplay between RABV and innate immunity is necessary to develop effective strategies to combat its infection. Here, we review the innate immune responses induced by RABV and illustrate the antagonism mechanisms of RABV to provide new insights for the control of rabies.

A Visual Assay of a Loop-Mediated Isothermal Amplification Based Vertical Immunoassay for SARS-CoV-2 RNA Detection.

SARS-CoV-2 is a novel coronavirus that has caused a global pandemic. To date, 504,907,616 people have been infected and developed coronavirus disease 2019 (COVID-19). A rapid and simple diagnostic method is needed to control this pandemic. In this study, a visual nucleic acid detection method combining reverse transcription loop-mediated isothermal amplification and a vertical flow visualization strip (RT-LAMP-VF) was successfully established and could detect 20 copies/µl of SARS-CoV-2 RNA transcript within 50 min at 61°C. This assay had no cross-reactivity with a variety of coronaviruses, including human coronavirus OC43, 229E, HKU1, NL63, severe acute respiratory syndrome-related coronavirus (SARSr-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and bat coronavirus HKU4, exhibiting very high levels of diagnostic sensitivity and specificity. Most strikingly, this method can be used for detecting multiple SARS-CoV-2 variants, including the Wuhan-Hu-1 strain, Delta, and Omicron variants. Compared with the RT-qPCR method recommended by the World Health Organization (WHO), RT-LAMP-VF does not require special equipment and is easy to perform. As a result, it is more suitable for rapid screening of suspected SARS-CoV-2 samples in the field and local laboratories.

Plant diversity in sedimentary DNA obtained from high-latitude (Siberia) and high-elevation lakes (China).

BACKGROUND: Plant diversity in the Arctic and at high altitudes strongly depends on and rebounds to climatic and environmental variability and is nowadays tremendously impacted by recent climate warming. Therefore, past changes in plant diversity in the high Arctic and high-altitude regions are used to infer climatic and environmental changes through time and allow future predictions. Sedimentary DNA (sedDNA) is an established proxy for the detection of local plant diversity in lake sediments, but still relationships between environmental conditions and preservation of the plant sedDNA proxy are far from being fully understood. Studying modern relationships between environmental conditions and plant sedDNA will improve our understanding under which conditions sedDNA is well-preserved helping to a.) evaluate suitable localities for sedDNA approaches, b.) provide analogues for preservation conditions and c.) conduct reconstruction of plant diversity and climate change. This study investigates modern plant diversity applying a plant-specific metabarcoding approach on sedimentary DNA of surface sediment samples from 262 lake localities covering a large geographical, climatic and ecological gradient. Latitude ranges between 25°N and 73°N and longitude between 81°E and 161°E, including lowland lakes and elevated lakes up to 5168 m a.s.l. Further, our sampling localities cover a climatic gradient ranging in mean annual temperature between -15°C and +18°C and in mean annual precipitation between 36- and 935 mm. The localities in Siberia span over a large vegetational gradient including tundra, open woodland and boreal forest. Lake localities in China include alpine meadow, shrub, forest and steppe and also cultivated areas. The assessment of plant diversity in the underlying dataset was conducted by a specific plant metabarcoding approach. NEW INFORMATION: We provide a large dataset of genetic plant diversity retrieved from surface sedimentary DNA from lakes in Siberia and China spanning over a large environmental gradient. Our dataset encompasses sedDNA sequence data of 259 surface lake sediments and three soil samples originating from Siberian and Chinese lakes. We used the established chloroplastidal P6 loop trnL marker for plant diversity assessment. The merged, filtered and assigned dataset includes 15,692,944 read counts resulting in 623 unique plant DNA sequence types which have a 100% match to either the EMBL or to the specific Arctic plant reference database. The underlying dataset includes a taxonomic list of identified plants and results from PCR replicates, as well as extraction blanks (BLANKs) and PCR negative controls (NTCs), which were run along with the investigated lake samples. This collection of plant metabarcoding data from modern lake sediments is still ongoing and additional data will be released in the future.

Factors controlling the oxygen isotopic composition of lacustrine authigenic carbonates in Western China: implications for paleoclimate reconstructions.

In the carbonate-water system, at equilibrium, the oxygen isotopic composition of carbonate is dependent not only on the temperature but also on the isotopic composition of host water in which the carbonate is formed. In this study, lake surface sediment and water samples were collected from 33 terminal lakes in Western China to evaluate controls on the oxygen isotopic composition of lacustrine authigenic carbonates (δ18Ocarb) and its spatial distribution. Our results show that water oxygen isotopic composition (δ18Owater) rather than lake summer water temperature (Twater), is the main determinant of δ18Ocarb, irrespective of whether oxygen isotope equilibrium is achieved. There are significant linear correlations between δ18Ocarb and elevation, as well as that between δ18Ocarb and latitude for lakes located on the Tibetan Plateau. In Western China, the spatial distribution of δ18Ocarb is consistent with that of δ18Owater, and is ultimately controlled by the isotopic composition of local precipitation (δ18Oprecipitation) that depends on the source of water vapor. Therefore, changes in δ18Ocarb can be predominantly interpreted as variations of δ18Owater, which in turn represent changes in δ18Oprecipitation for paleoclimate reconstructions in this region, and may be relevant to studies of other areas.

A Potential Inhibitor of MCR-1: An Attempt to Enhance the Efficacy of Polymyxin Against Multidrug-Resistant Bacteria.

The irrational use of broad-spectrum antibiotics has led to increasing resistance of bacteria to antibiotics, and the emergence of the plasmid-mediated colistin resistance gene mcr-1 has led to the dilemma of infections with no available cure. Here, we have found a potential MCR-1 inhibitor for use against infections caused by MCR-1 positive resistant bacteria. A checkerboard MIC (minimum inhibitory concentration) assay, growth curve assay, kill curve assay, cytotoxicity assay, molecular dynamics simulation analysis, Western blot assay and mouse pneumonia model in vivo protection rate assay were used to evaluate the synergy effect between genistein and polymyxins. The results showed that genistein could restore the bactericidal activity against MCR-1-positive strains for which there was no antibacterial activity, and reduce the bacterial load to some extent. Genistein does not inhibit the expression of MCR-1, but inhibits the binding of MCR-1 to its substrate by binding to the amino acids of the active region of MCR-1, thereby inhibiting the biological activity of MCR-1. The in vivo results also showed that the protection rate of mice treated with the combination therapy of genistein and polymyxins increased by 20% compared to that of mice treated with polymyxins alone. Our results confirm that genistein is an inhibitor of MCR-1 and promote its potential use in combination with polymyxins to treat severe infections caused by MCR-1 positive Enterobacteriaceae.

Theaflavin-3,3´-digallate increases the antibacterial activity of ß-lactam antibiotics by inhibiting metallo-ß-lactamase activity.

Metallo-ß-lactamases (MBLs) are some of the best known ß-lactamases produced by common Gram-positive and Gram-negative pathogens and are crucial factors in the rise of bacterial resistance against ß-lactam antibiotics. Although many types of ß-lactamase inhibitors have been successfully developed and used in clinical settings, no MBL inhibitors have been identified to date. Nitrocefin, checkerboard and time-kill assays were used to examine the enzyme behaviour in vitro. Molecular docking calculation, molecular dynamics simulation, calculation of the binding free energy and ligand-residue interaction decomposition were used for mechanistic research. The behaviour of the enzymes in vivo was investigated by a mouse infection experiment. We showed that theaflavin-3,3´-digallate (TFDG), a natural compound lacking antibacterial activities, can inhibit the hydrolysis of MBLs. In the checkerboard and time-kill assays, we observed a synergistic effect of TFDG with ß-lactam antibiotics against methicillin-resistant Staphylococcus aureus BAA1717. Molecular dynamics simulations were used to identify the mechanism of the inhibition of MBLs by TFDG, and we observed that the hydrolysis activity of the MBLs was restricted by the binding of TFDG to Gln242 and Ser369. Furthermore, the combination of TFDG with ß-lactam antibiotics showed effective protection in a mouse Staphylococcus aureus pneumonia model. These findings suggest that TFDG can effectively inhibit the hydrolysis activity of MBLs and enhance the antibacterial activity of ß-lactam antibiotics against pathogens in vitro and in vivo.

Position and orientation of the westerly jet determined Holocene rainfall patterns in China.

Proxy-based reconstructions and modeling of Holocene spatiotemporal precipitation patterns for China and Mongolia have hitherto yielded contradictory results indicating that the basic mechanisms behind the East Asian Summer Monsoon and its interaction with the westerly jet stream remain poorly understood. We present quantitative reconstructions of Holocene precipitation derived from 101 fossil pollen records and analyse them with the help of a minimal empirical model. We show that the westerly jet-stream axis shifted gradually southward and became less tilted since the middle Holocene. This was tracked by the summer monsoon rain band resulting in an early-Holocene precipitation maximum over most of western China, a mid-Holocene maximum in north-central and northeastern China, and a late-Holocene maximum in southeastern China. Our results suggest that a correct simulation of the orientation and position of the westerly jet stream is crucial to the reliable prediction of precipitation patterns in China and Mongolia.

Discovery of a potential MCR-1 inhibitor that reverses polymyxin activity against clinical mcr-1-positive Enterobacteriaceae.

The recent emergence of the plasmid-mediated colistin resistance gene mcr-1 poses a substantial clinical threat to the severe infections caused by CRE (Carbapenem Resistant Enterobacteriaceae), as the treatment failure of the mcr-1-positive CRE "Superbug" most likely occurs by using the combination of carbapenem and polymixins. Therefore, our study aims to seek a potent MCR-1 inhibitor to fight this infection. A checkerboard MIC (Minimum Inhibitory Concentration) assay, time-killing assay, MPNP (Modified rapid polymyxin Nordmann/Poirel) test, combined disk test and molecular modelling analysis were performed on different mcr-1-positive strains to confirm the synergistic effects of the combination of colistin and osthole (OST). And a thigh mouse infection model was also used to evaluate such synergies. We identified that OST regained the bactericidal activity of polymyxins (FIC (Fractional Inhibitory Concentration) index = 0.11±0.04 - 0.29±0.10) against mcr-1-positive Enterobacteriaceae including Escherichia coli and Klebsiella pneumoniae. The in-vitro time-killing assays showed that either OST or polymyxins failed to eradicate mcr-1-positive Enterobacteriaceae, but the combination eliminated mcr-1-positive Enterobacteriaceae by 3-7-h post-inoculation. The mouse infection model demonstrated that the combination therapy significantly reduced the bacterial load in the thighs following subcutaneous administration. Our results established that OST is a promising natural compound that could be used to extend the life of polymyxins and to tackle the inevitability of serious infections caused by polymyxin-resistant bacteria.

Organic and inorganic carbon and their stable isotopes in surface sediments of the Yellow River Estuary.

Studying the carbon dynamics of estuarine sediment is crucial to understanding of carbon cycle in the coastal ocean. This study is to evaluate the mechanisms regulating the dynamics of organic (TOC) and inorganic carbon (TIC) in surface sediment of the Yellow River Estuary (YRE). Based on data of 15 surface sediment cores, we found that TIC (6.3-20.1 g kg-1) was much higher than TOC (0.2-4.4 g kg-1). Both TOC and TIC were generally higher to the north than to the south, primarily due to the differences in kinetic energy level (i.e., higher to the south). Our analysis suggested that TOC was mainly from marine sources in the YER, except in the southern shallow bay where approximately 75% of TOC was terrigenous. The overall low levels of TOC were due to profound resuspension that could cause enhanced decomposition. On the other hand, high levels of TIC resulted partly from higher rates of biological production, and partly from decomposition of TOC associated with sediment resuspension. The isotopic signiture in TIC seems to imply that the latter is dominant in forming more TIC in the YRE, and there may be transfer of OC to IC in the water column.

Heavy Metal Pollution in Settled Dust Associated with Different Urban Functional Areas in a Heavily Air-Polluted City in North China.

Understanding variations of heavy metals in atmospheric particles between different functional areas is significant for pollution control and urban planning in cities. To reveal pollution and spatial distribution of heavy metals in atmospheric particles from different urban functional areas in Shijiazhuang in North China, 43 settled dust samples were collected over the main urban area and heavy metal concentrations were determined in their <63 µm fractions using an ICP-OES. The results suggest that Cr, Mn, Fe, Co, Ni, and V in the dust are not or slightly enriched and their concentrations vary slightly between different sites, implying their natural origins; whereas Cu, Zn, Cd, and Pb are often notably enriched and their concentrations vary significantly between different functional areas, indicating their anthropogenic sources. Integrated pollution indexes (IPIs) of the ten heavy metals are 2.7-13.6 (5.7 ± 2.2), suggesting high or very high pollution levels of most dust. Relatively lower IPIs occur mainly in the administration-education area, the commercial area, and other unclassified sites; while peaks occur mainly in the North Railway Station, the northeastern industrial area, and some sites near heavily trafficked areas, implying the significant influence of intensive industrial (including coal combustion) and traffic activities on atmospheric heavy metal accumulation. These results suggest a clear need of mitigating atmospheric heavy metal pollution via controlling emissions of toxic metals (especially Cd and Pb) from industrial and traffic sources in the city.

Preliminary Assessment of Health Risks of Potentially Toxic Elements in Settled Dust over Beijing Urban Area.

To examine levels, health risks, sources, and spatial distributions of potentially toxic elements in settled dust over Beijing urban area, 62 samples were collected mostly from residential building outdoor surfaces, and their <63 µm fractions were measured for 12 potentially toxic elements. The results show that V, Cr, Mn, Co, Ni, and Ba in dust are from predominantly natural sources, whereas Cu, Zn, As, Cd, Sb, and Pb mostly originate from anthropogenic sources. Exposure to these elements in dust has significant non-cancer risks to children but insignificant to adults. Cancer risks of Cr, Co, Ni, As, and Cd via inhalation and dermal contact are below the threshold of 10(-6)-10(-4) but As via dust ingestion shows a tolerable risk. The non-cancer risks to children are contributed mainly (75%) by As, Pb, and Sb, and dominantly (92%) via dust ingestion, with relatively higher risks mainly occurring in the eastern and northeastern Beijing urban areas. Although Cd, Zn, and Cu in dust are heavily affected by anthropogenic sources, their health risks are insignificant. Source appointments suggest that coal burning emissions, the dominant source of As, are likely the largest contributors to the health risk, and traffic-related and industrial emissions are also important because they contribute most of the Pb and Sb in dust.

Rapid climate fluctuations over the past millennium: evidence from a lacustrine record of Basomtso Lake, southeastern Tibetan Plateau.

Abrupt climate changes and fluctuations over short time scales are superimposed on long-term climate changes. Understanding rapid climate fluctuations at the decadal time scale over the past millennium will enhance our understanding of patterns of climate variability and aid in forecasting climate changes in the future. In this study, climate changes on the southeastern Tibetan Plateau over the past millennium were determined from a 4.82-m-long sediment core from Basomtso Lake. At the centennial time scale, the Medieval Climate Anomaly (MCA), Little Ice Age (LIA) and Current Warm Period (CWP) are distinct in the Basomtso region. Rapid climate fluctuations inferred from five episodes with higher sediment input and likely warmer conditions, as well as seven episodes with lower sediment input and likely colder conditions, were well preserved in our record. These episodes with higher and lower sediment input are characterized by abrupt climate changes and short time durations. Spectral analysis indicates that the climate variations at the centennial scale on the southeastern Tibetan Plateau are influenced by solar activity during the past millennium.

Identification of photosynthetic plankton communities using sedimentary ancient DNA and their response to late-Holocene climate change on the Tibetan Plateau.

Sediments from Tibetan lakes in NW China are potentially sensitive recorders of climate change and its impact on ecosystem function. However, the important plankton members in many Tibetan Lakes do not make and leave microscopically diagnostic features in the sedimentary record. Here we established a taxon-specific molecular approach to specifically identify and quantify sedimentary ancient DNA (sedaDNA) of non-fossilized planktonic organisms preserved in a 5-m sediment core from Kusai Lake spanning the last 3100 years. The reliability of the approach was validated with multiple independent genetic markers. Parallel analyses of the geochemistry of the core and paleo-climate proxies revealed that Monsoon strength-driven changes in nutrient availability, temperature, and salinity as well as orbitally-driven changes in light intensity were all responsible for the observed temporal changes in the abundance of two dominant phytoplankton groups in the lake, Synechococcus (cyanobacteria) and Isochrysis (haptophyte algae). Collectively our data show that global and regional climatic events exhibited a strong influence on the paleoecology of phototrophic plankton in Kusai Lake.

A less or more dusty future in the Northern Qinghai-Tibetan Plateau?

Dust plays an important role in climate changes as it can alter atmospheric circulation, and global biogeochemical and hydrologic cycling. Many studies have investigated the relationship between dust and temperature in an attempt to predict whether global warming in coming decades to centuries can result in a less or more dusty future. However, dust and temperature changes have rarely been simultaneously reconstructed in the same record. Here we present a 1600-yr-long quantitative record of temperature and dust activity inferred simultaneously from varved Kusai Lake sediments in the northern Qinghai-Tibetan Plateau, NW China. At decadal time scale, our temperature reconstructions are generally in agreement with tree-ring records from Karakorum of Pakistan, and temperature reconstructions of China and North Hemisphere based on compilations of proxy records. A less or more dusty future depends on temperature variations in the Northern Qinghai-Tibetan Plateau, i.e. weak and strong dust activities at centennial time scales are well correlated with low and high June-July-August temperature (average JJA temperature), respectively. This correlation means that stronger summer and winter monsoon should occur at the same times in the northern Qinghai-Tibetan Plateau.

Phylogenetic beta diversity in bacterial assemblages across ecosystems: deterministic versus stochastic processes.

Increasing evidence has emerged for non-random spatial distributions of microbes, but knowledge of the processes that cause variation in microbial assemblage among ecosystems is lacking. For instance, some studies showed that deterministic processes such as habitat specialization are important, while other studies hold that bacterial communities are assembled by stochastic forces. Here we examine the relative influence of deterministic and stochastic processes for bacterial communities from subsurface environments, stream biofilm, lake water, lake sediment and soil using pyrosequencing of the 16S ribosomal RNA gene. We show that there is a general pattern in phylogenetic signal in species ecological niches across recent evolutionary time for all studied habitats, enabling us to infer the influences of community assembly processes from patterns of phylogenetic turnover in community composition. The phylogenetic dissimilarities among-habitat types were significantly higher than within them, and the communities were clustered according to their original habitat types. For communities within-habitat types, the highest phylogenetic turnover rate through space was observed in subsurface environments, followed by stream biofilm on mountainsides, whereas the sediment assemblages across regional scales showed the lowest turnover rate. Quantifying phylogenetic turnover as the deviation from a null expectation suggested that measured environmental variables imposed strong selection on bacterial communities for nearly all sample groups. For three sample groups, spatial distance reflected unmeasured environmental variables that impose selection, as opposed to spatial isolation. Such characterization of spatial and environmental variables proved essential for proper interpretation of partial Mantel results based on observed beta diversity metrics. In summary, our results clearly indicate a dominant role of deterministic processes on bacterial assemblages and highlight that bacteria show strong habitat associations that have likely emerged through evolutionary adaptation.