Upregulation of the Tim-3/Galectin-9 Pathway of T Cell Exhaustion in Chronic Hepatitis B Virus Infection

The S-type lectin galectin-9 binds to the negative regulatory molecule Tim-3 on T cells and induces their apoptotic deletion or functional inactivation. We investigated whether galectin-9/Tim-3 interactions contribute to the deletion and exhaustion of the antiviral T cell response in chronic hepatitis B virus infection (CHB). We found Tim-3 to be expressed on a higher percentage of CD4 and CD8 T cells from patients with CHB than healthy controls (p<0.0001) and to be enriched on activated T cells and those infiltrating the HBV-infected liver. Direct ex vivo examination of virus-specific CD8 T cells binding HLA-A2/peptide multimers revealed that Tim-3 was more highly upregulated on HBV-specific CD8 T cells than CMV-specific CD8 T cells or the global CD8 T cell population in patients with CHB (p<0.001) or than on HBV-specific CD8 after resolution of infection. T cells expressing Tim-3 had an impaired ability to produce IFN-γ and TNF-α upon recognition of HBV-peptides and were susceptible to galectin-9-triggered cell death in vitro. Galectin-9 was detectable at increased concentrations in the sera of patients with active CHB-related liver inflammation (p = 0.02) and was strongly expressed by Kupffer cells within the liver sinusoidal network. Tim-3 blockade resulted in enhanced expansion of HBV-specific CD8 T cells able to produce cytokines and mediate cytotoxicity in vitro. Blocking PD-1 in combination with Tim-3 enhanced the number of patients from whom functional antiviral responses could be recovered and/or the strength of responses, indicating that these co-inhibitory molecules play a non-redundant role in driving T cell exhaustion in CHB. Patients taking antivirals able to potently suppress HBV viraemia continued to express Tim-3 on their T cells and respond to Tim-3 blockade. In summary, both Tim-3 and galectin-9 are increased in CHB and may contribute to the inhibition and deletion of T cells as they infiltrate the HBV-infected liver.     

Cloudwater Inputs of Nitrogen to Forest Ecosystems in Southern Chile: Forms, Fluxes, and Sources

Nitrogen (N) has been considered a limiting nutrient to many aquatic and terrestrial ecosystems. However, human activity has resulted in increased atmospheric N deposition worldwide such that N pollution is now altering ecosystem function in many locations. Research on atmospheric deposition has focused primarily on inorganic nitrogen (DIN; NH₄ ⁺-N + NO₃ ⁻-N) via rainwater and dry deposition as the main N input to ecosystems. Recently, organic N (ON) has been shown to be an important constituent in rainwater or dry deposition. Here we show that ON dominated (66%) total N in cloudwater from a remote site in southern Chile. Cloudwater from more human-impacted sites in northeastern USA had lower ON concentrations and DIN was dominant. We estimate that cloudwater delivers up to 2 kg ha⁻¹ DIN and 9 kg ha⁻¹ ON annually, compared to less than 1 kg ha⁻¹ of DIN deposition via rainwater, thus it may contribute substantially to the N-economy of Chilean coastal forests. We also suggest that the adjacent ocean, where biologic productivity is high, may be a major source of N in Chilean cloudwater. This proposed marine-terrestrial flux via cloud deposition has not previously been identified and may be an example of the ocean feeding the forest. We suggest that this type of cross boundary flux may be common in other upwelling zones, such as along the west coasts of Africa, North and South America and east India, and warrants further substantiation and investigation. Received 30 June 2000; accepted 18 October 2000     

硫化氢在植物中的生理功能及作用机制

硫化氢(H₂S)是继一氧化氮(NO)和一氧化碳(CO)之后第3个气体信号分子, 在植物体内参与许多重要的生理活动, 能够促进植物光合作用和有机物的积累, 缓解各种生物和非生物胁迫并促进植物生长发育。该文综述了植物体内H₂S的物理化学性质、产生机制、主要生理功能和作用机制以及与其它信号分子的互作关系, 并展望了H₂S信号分子的研究前景。     

CSPP Is a Ciliary Protein Interacting with Nephrocystin 8 and Required for Cilia Formation

We described previously the cell cycle- and microtubule-related functions of two splice isoforms of the centrosome spindle pole-associated protein (CSPP and CSPP-L). Here, we show that endogenous CSPP isoforms not only localize to centrosomes and the midbody in cycling cells but also extend to the cilia axoneme in postmitotic resting cells. They are required for ciliogenesis in hTERT-RPE1 cells in vitro and are expressed in ciliated renal, retinal, and respiratory cells in vivo. We report that CSPP isoforms require their common C-terminal domain to interact with Nephrocystin 8 (NPHP8/RPGRIP1L) and to form a ternary complex with NPHP8 and NPHP4. We find CSPP-L to be required for the efficient localization of NPHP8 but not NPHP4 to the basal body. The ciliogenesis defect in hTERT-RPE1 cells is, however, not mediated through loss of NPHP8. Similar to the effects of ectopical expression of CSPP-L, cilia length increased in NPHP8-depleted cells. Our results thus suggest that CSPP proteins may be involved in further cytoskeletal organization of the basal body and its primary cilium. To conclude, we have identified a novel, nonmitotic function of CSPP proteins placing them into a ciliary protein network crucial for normal renal and retinal tissue architecture and physiology.     

Glucose uptake by Cellulomonas fimi

Glucose uptake by whole-cell suspension of the facultative anaerobe Cellulomonas fimi, which was two-fold higher under aerobic conditions than under N₂ or H₂, was inhibited by inhibitors of electron transport and ATP synthesis and, particularly, by proton and metal ion ionophores. A variety of sugars, including 2-deoxyglucose, did not inhibit glucose uptake but cellobiose was a non-competitive inhibitor. Cells grown on cellobiose medium transported glucose at one half the rate of glucose-grown cells. Cellulomonas fimi has a highly specific active system for glucose transport.     

Plant community dynamics relative to the changing distribution of a highly invasive species, <Emphasis Type="Italic">Eichhornia crassipes</Emphasis>: a remote sensing perspective

Eradicating or controlling invasive alien species has frequently had unintended consequences, such as proliferation of other invasive species or loss of ecosystem function. We explore this problem using a case study of a highly invasive floating aquatic macrophyte, water hyacinth (Eichhornia crassipes), in the Sacramento-San Joaquin Delta of California. We used 5 years of remote sensing data to perform change detection analysis to study plant community dynamics contemporaneous with changes in water hyacinth cover. Our results show that as water hyacinth cover decreased, submerged aquatic plant (SAP) cover increased and vice versa. This effect was strongest in large patches of water hyacinth. We found no evidence that the native floating aquatic species, pennywort (Hydrocotyle umbellata), benefitted from reducing cover of water hyacinth. In most years, pennywort cover either showed no trend or followed the same trajectory as water hyacinth cover. In this study a decrease in cover of water hyacinth most often resulted in colonization by SAP species with some habitat returning to open water.     

Sixth mycelial fraction acetone (6-MFA), an interferon inducer modulates acrylamide neurotoxicity

A single i.p. administration of an immunomodulatory agent 6-MFA (a biological response modifier and antiviral agent of fungal origin, 10 mg/100g b.wt.), on 5th day of repeated acrylamide (ACR, 50 mg/kg b.wt.) treatment significantly protected rats against its specific neurotoxic effects. Corpus striatal 3H-spiperone binding elevated (24%) while glutathione-S-transferase (GST) activity decreased (33%) in ACR group but values were markedly restored in 6-MFA alone and co-exposed group. Development of hind limb paralysis was also protected by 6-MFA. Results warrant the possible involvement of immune mechanisms and certain other factors such as lymphokines, hormones and microglia at the target site, which in turn facilitate the repair mechanism suggesting a therapeutic role of 6-MFA in clinical cases of toxic neuropathies in future.     

Multigenerational maternal effect on diapause induction in Trichogramma species (Hymenoptera: Trichogrammatidae)

Maternal photoperiodic response is known to influence the percentage of diapausing prepupae in Trichogramma species. However, the influence of several preceding generations has not yet been studied. We have investigated the stability of photoperiod-induced changes in multiple generations of Trichogramma buesi Voegele and Trichogramma principium Sug. et Sor. Short-day conditions during preimaginal development induced an increase in the percentage of diapausing progeny and grand progeny of both Trichogramma species. A similar trend was also detected in the fourth and fifth generations, but the response was weak although statistically significant. This grand-grandmaternal photoperiodic effect (which has not been demonstrated before for Trichogramma or for any other insect parasitoid) is most probably based on the transgenerational transmission of variations in DNA expression. We conclude that in mass rearing, to facilitate diapause induction before cold storage, it is advisable to rear both maternal and grandmaternal generations under the short-day conditions. In scientific studies, several generations preceding the experiment should be kept under equal conditions to exclude multigenerational maternal effects.