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Large, sediment-laden floods in mountainous terrain can have disastrous consequences and play important roles in landscape evolution. These events often unfold as a series of interconnected processes, but understanding of such “hazard cascades” has been hampered by lack of quantitative data on sediment movement. Here, we use a time series of high-resolution satellite imagery to quantify erosion and aggradation during the 2021 Melamchi Khola Floods in the Himalaya of central Nepal, providing a unique sediment budget for such an event. Our analysis reveals massive headwater erosion via remobilization of Gorkha landslides, gullying, debris-flows, and incision of glacial deposits. Unlike many other high mountain floods, the widely distributed erosion suggests this event was not primarily driven by a single source, e.g., glacial lake or landslide dam failure. High sediment supply caused aggradation in a high-elevation, low-relief glacial valley and triggered catastrophic incision into associated ancient fills. As this material was transported downstream, it caused further riverbed incision that in turn resulted in failures of surrounding hillslopes. Further downstream, as river steepness diminished, the main channel in the lower basin was widened by 3-5-fold and aggraded by ~ 5–20 m. However, deposition in the Melamchi Khola was not enough to accommodate the vast amount of flood material, and over 70% was delivered from the Melamchi Khola to the downstream Indrawati basin. Our sediment budget provides rare insight into the chain of events involved in a massive flood and helps shed light on how such floods can magnify hazard and reshape the fluvial landscape.

Burkholderia pseudomallei: which causes melioidosis with high mortality in humans, has become a global public health concern. Recently, infection-driven lipid droplet accumulation has been related to the progression of host-pathogen interactions, and its contribution to the pathogenesis of infectious disease has been investigated. Here, we demonstrated that B. pseudomallei infection actively induced a time-dependent increase in the number and size of lipid droplets in human lung epithelial cells and macrophages. We also found that lipid droplet accumulation following B. pseudomallei infection was associated with downregulation of PNPLA2/ATGL (patatin like phospholipase domain containing 2) and lipophagy inhibition. Functionally, lipid droplet accumulation, facilitated via PNPLA2 downregulation, inhibited macroautophagic/autophagic flux and, thus, hindered autophagy-dependent inhibition of B. pseudomallei infection in lung epithelial cells. Mechanistically, we further revealed that nuclear receptor NR1D2 might be involved in the suppression of PNPLA2 after cell exposure to B. pseudomallei. Taken together, our findings unraveled an evolutionary strategy, by which B. pseudomallei interferes with the host lipid metabolism, to block autophagy-dependent suppression of infection. This study proposes potential targets for clinical therapy of melioidosis. Abbreviations: 3-MA: 3-methyladenine; ACTB: actin beta; ATG7: autophagy related 7; B. pseudomallei: Burkholderia pseudomallei; CFU: colony-forming unit; DG: diglyceride; FASN: fatty acid synthase; GFP: green fluorescent protein; LAMP1: lysosomal associated membrane protein 1; LC-MS/MS: liquid chromatography-tandem mass spectrometry; LD: lipid droplet; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MG: monoglyceride; MOI: multiplicity of infection; mRFP: monomeric red fluorescent protein; NR1D2: nuclear receptor subfamily 1 group D member 2; p.i., post-infection; PLIN2/ADRP: perilipin 2; PNPLA2/ATGL: patatin like phospholipase domain containing 2; Rapa: rapamycin; SQSTM1/p62: sequestosome 1; shRNA: short hairpin RNA; TEM: transmission electron microscopy; TG: triglyceride

Burkholderia pseudomallei is a zoonotic pathogen that usually affects patients' lungs and causes serious melioidosis. The interaction of B. pseudomallei with its hosts is complex, and cellular response to B. pseudomallei infection in humans still remains to be elucidated. In this study, transcriptomic profiling of B. pseudomallei-infected human lung epithelial A549 cells was performed to characterize the cellular response dynamics during the early infection (EI) stage. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed by using the online databases DAVID 6.8 and KOBAS 3.0. Real-time quantitative PCR and western blot were used for validation experiments. Compared with the negative control group (NC), a set of 36 common genes varied over time with a cut-off level of 1.5-fold change, and a P-value < 0.05 was identified. Bioinformatics analysis indicated that the PERK-mediated unfolded protein response (UPR) was enriched as the most noteworthy biological process category, which was enriched as a branch of UPR in the signaling pathway of protein processing in the endoplasmic reticulum. Other categories, such as inflammatory responses, cell migration, and apoptosis, were also focused. The molecular chaperone Bip (GRP78), PERK, and PERK sensor-dependent phosphorylation of eIF2α (p-eIF2α) and ATF4 were verified to be increasing over time during the EI stage, suggesting that B. pseudomallei infection activated the PERK-mediated UPR in A549 cells. Collectively, these results provide important initial insights into the intimate interaction between B. pseudomallei and lung epithelial cells, which can be further explored toward the elucidation of the cellular mechanisms of B. pseudomallei infections in humans.

Antibiotic resistance represents a global health crisis for humans, animals, and for the environment. Transmission of antibiotic resistance through environmental pathways is a cause of concern. In this study, quantitative PCR and culture-dependent bacteriological methods were used to detect the abundance of antibiotic resistance genes (ARGs) and the quantity of culturable heterotrophic antibiotic-resistant bacteria (ARB) in marine fish farming areas. The results indicated that sul and tet family genes were widely distributed in marine fish farming areas of Hainan during both rearing and harvesting periods. Specifically, sul1 and tetB were the most dominant ARGs. The total abundance of ARGs increased significantly from the rearing to the harvesting period. A total of 715 ARB strains were classified into 24 genera, within these genera Vibrio, Acinetobacter, Pseudoalteromonas, and Alteromonas are opportunistic pathogens. High bacterial resistance rate to oxytetracycline (OT) was observed. The numbers of OT- and enrofloxacin-resistant bacteria dropped significantly from rearing the period to the harvesting. The co-occurrence pattern showed that Ruegeria and tetB could be indicators of ARB and ARGs, respectively, which were found in the same module. Redundancy analysis indicated that salinity was positively correlated with the most dominant ARB, and was negatively correlated with the most dominant ARGs. These findings demonstrated the prevalence and persistence of ARGs and ARB in marine fish farming areas in China.

Background: Burkholderia pseudomallei causes melioidosis and usually affects patients’ lungs, its persistent infection promotes the fusion of host cells, leading to the formation of multinucleated giant cells (MGCs) at the late infected stage. In this study, the global transcriptomic responses of B. pseudomallei infection of a human lung epithelial A549 cell model with different infected stages were investigated by means of microarray analysis to further elucidate the host cellular factors involved in the occurrence and development of the event. Results: A set of 35 common differential expression genes (DEGs) in EI and LI on the mRNA level applying a cut-off level of 1.5-fold change and a p-value < 0.05 were observed. Microarray data were further verified by Real-Time quantitative PCR (RT-qPCR). GO classification and pathway enrichment analysis revealed these DEGs mainly involved in inflammatory response related processes, such as cellular response to tumor necrosis factor, cellular response to lipopolysaccharide, positive regulation of NF-κB transcription factor activity. p-eIF2α, ATF4,NF-κB2(p52) and IL-1β were next selected to be validated by western bloting, which indicated B. pseudomallei could activate the eIF2α-ATF4 axis and NF-κB2 pathway in A549 cells. Conclusion: Our data shed light on the transcriptome dynamics of A549 cells which persistently infected with B. pseudomallei and suggested that the formation of MGCs may be a means for B. pseudomallei to manipulate the host's inflammation and stress response to adapt to intracellular life.

Burkholderia pseudomallei is a gram-negative, facultative intracellular bacterium, which causes a disease known as melioidosis. Professional phagocytes represent a crucial first line of innate defense against invading pathogens. Uptake of pathogens by these cells involves the formation of a phagosome that matures by fusing with early and late endocytic vesicles, resulting in killing of ingested microbes. Host Rab GTPases are central regulators of vesicular trafficking following pathogen phagocytosis. However, it is unclear how Rab GTPases interact with B. pseudomallei to regulate the transport and maturation of bacterial-containing phagosomes. Here, we showed that the host Rab32 plays an important role in mediating antimicrobial activity by promoting phagosome maturation at an early phase of infection with B. pseudomallei. And we demonstrated that the expression level of Rab32 is increased through the downregulation of the synthesis of miR-30b/30c in B. pseudomallei infected macrophages. Subsequently, we showed that B. pseudomallei resides temporarily in Rab32-positive compartments with late endocytic features. And Rab32 enhances phagosome acidification and promotes the fusion of B. pseudomallei-containing phagosomes with lysosomes to activate cathepsin D, resulting in restricted intracellular growth of B. pseudomallei. Additionally, Rab32 mediates phagosome maturation depending on its guanosine triphosphate/guanosine diphosphate (GTP/GDP) binding state. Finally, we report the previously unrecognized role of miR-30b/30c in regulating B. pseudomallei-containing phagosome maturation by targeting Rab32 in macrophages. Altogether, we provide a novel insight into the host immune-regulated cellular pathway against B. pseudomallei infection is partially dependent on Rab32 trafficking pathway, which regulates phagosome maturation and enhances the killing of this bacterium in macrophages., Author summary Burkholderia pseudomallei is a gram-negative intracellular bacterium and the etiological agent of melioidosis. Little is known about the host innate immune system, which is engaged in a continuous battle against this pathogen and may contribute to the outcomes of melioidosis. Recently, Rab32, a Rab GTPase was shown to be a critical regulator of a host defense pathway against intracellular bacterial pathogens. However, the exact mechanism of how Rab32 contributes to the restriction of intracellular pathogens is not completely understood. In this study, we determined that the infection of macrophages with B. pseudomallei resulted in the upregulation of Rab32 expression through the inhibition of miR-30b/30c expression. Subsequently, Rab32 is recruited to the B. pseudomallei-containing phagosomes and promotes the fusion of the phagosomes with lysosomes, which results in the increased exposure of B. pseudomallei to lysosomal acid hydrolases CTSD, thus limiting the intracellular growth of B. pseudomallei at an early phase of infection in macrophages. Our findings establish for the first time that Rab32 plays an important role in suppressing the intracellular replication of B. pseudomallei by modulating phagosome maturation in macrophages, providing a new insight into the host defense mechanisms against B. pseudomallei infection.

Background: The role of serum uric acid (SUA) level in the progression of Immunoglobulin A nephropathy (IgAN) remains controversial. Methods: In a cohort of 1,965 cases with biopsy-proven IgAN, we examined the associations of SUA concentration with the primary outcome of a composite of all-cause mortality or kidney failure (defined as a reduction of estimated glomerular filtration rate [eGFR] by 40% from baseline, requirements for dialysis and transplantation), or the outcome of kidney failure alone, assessed using Cox and logistic regression models, respectively, with adjustment for confounders. Results: At baseline, the mean age was 33.37 ± 11.07 years, eGFR was 101.30 ± 30.49 mL/min/1.73 m2, and mean uric acid level was 5.32 ± 1.76 mg/dL. During a median of 7-year follow-up, 317 cases reached the composite outcome of all-cause mortality (5 deaths) or kidney failure (36 cases of dialysis, 5 cases of renal transplantation, and 271 cases with reduction of eGFR by 40% from baseline). After adjustment for demographic and IgAN specific covariates and treatments, a higher quartile of uric acid was linearly associated with an increased risk of the primary outcome (highest versus lowest quartile, hazard ratio [HR] 2.39; 95% CI 1.52–3.75) and kidney failure (highest versus lowest quartile, HR 2.55; 95% CI 1.62–4.01) in the Cox proportional hazards regression models. In the continuous analysis, a 1 mg/dL greater uric acid level was associated with 16% increased risk of primary outcome (HR 1.16, 95% CI 1.07–1.25) and 17% increased risk of kidney failure (HR 1.17, 95% CI 1.08–1.27), respectively, in the fully adjusted model. The multivariate ­logistic regression analyses for the sensitive analyses drew consistent results. In the subgroup analyses, significant interactions were detected that patients with mean arterial pressure (MAP) < 90 mm Hg or mesangial hypercellularity had a higher association of SUA with the incidence of the primary outcome than those with MAP ≥90 mm Hg or those without mesangial hypercellularity respectively. Hyperuricemia was not significantly associated with the risk of developing the primary outcome in elder patients (≥32 years old), patients with eGFR < 90 mL/min or with tubular atrophy/interstitial fibrosis. Conclusions: SUA level may be positively associated with the progression of IgAN. It was noticeable that the association of hyperuricemia with IgAN progression was less significant in patients with elder age, lower eGFR, or tubular atrophy/interstitial fibrosis, which may be due to some more confounders in association with the IgA progression in these patients. Future prospective studies are warranted to confirm these findings and to investigate the underlying mechanisms.

The translocated intimin receptor (Tir) is a canonical type III secretion system effector, secreted by the enterohemorrhagic Escherichia coli (E. coli). This receptor alters the regular cellular processing of host cells, to promote intracellular bacterial replication and evasion of the host immune system. Tir is translocated and integrated into the host cell plasma membrane, a process required for its pathogenic activity in these cells, however, the underlying mechanisms of how this occurs remain to be elucidated. The present study used immunofluorescence and immunoelectron microscopy to demonstrate that the Tir of enterohemorrhagic E. coli was localized to the plasma membrane and colocalized with the 58K Golgi protein of the host cells. Treatment with brefeldin A destroyed the Golgi structure, inhibited the formation of actin pedestal and blocked the localization of Tir on the host cell plasma membrane. The results of the present study suggested that Tir is translocated to the host plasma membrane in a Golgi‑dependent manner. It may mimic the activities of eukaryotic secretory proteins in order to make use of the Golgi apparatus for transportation and integration into the plasma membrane. These findings reveal a novel trafficking pathway for the translocation of bacterial secretory effectors to their specific subcellular compartments.

Annonaceous acetogenins are a large family of naturally occurring polyketides exhibiting remarkable anticancer activities. The first generation of annonaceous acetogenin mimetic (1, AA005) exhibits comparable activity as that of natural products and presents much higher selectivity between cancer and normal cells. In this work, we report the design, synthesis, and evaluation of a new series of compound 1 analogues in which a variety of conformation-constrained fragments were embedded in the left hydrocarbon chain part. Compound 7 bearing a biphenyl moiety was identified to exhibit more potent antiproliferative activity and preferentially target cancer cells over normal cells and thus represents a new lead for further optimization.

Linear annonaceous acetogenin mimetic AA005 has been found to exhibit potent antitumor activity and significant selectivity between human normal and cancerous cells. Utilizing the concept of Click chemistry, a convergent modular fragment-assembly approach has been newly developed and successfully applied to the synthesis of three representative AA005-like molecules via formation of small nitrogen-containing heterocycles or amide bond. These nitrogen-containing analogues were found to exhibit low micromolar inhibitory activities against the growth of several cancer cell lines.