ABSTRACT

While there is no effective vaccine against Chlamydia trachomatis infection, previous work has demonstrated the importance of C. trachomatis-specific CD4⁺ T cells (NR1 T cells) in pathogen clearance. Specifically, NR1 T cells have been shown to be protective in mice, and this protection depends on the host’s ability to sense the cytokine gamma interferon (IFN-). However, it is unclear what role NR1 production or sensing of IFN- plays in T cell homing to the genital tract or T cell-mediated protection against C. trachomatis. Using two-photon microscopy and flow cytometry, we found that naive wild-type (WT), IFN-^–/–, and IFN-R^–/– NR1 T cells specifically home to sections in the genital tract that contain C. trachomatis. We also determined that protection against infection requires production of IFN- from either NR1 T cells or endogenous cells, further highlighting the importance of IFN- in clearing C. trachomatis infection.

IMPORTANCE Chlamydia trachomatis is an important mucosal pathogen that is the leading cause of sexually transmitted bacterial infections in the United States. Despite this, there is no vaccine currently available. In order to develop such a vaccine, it is necessary to understand the components of the immune response that can lead to protection against this pathogen. It is well known that antigen-specific CD4⁺ T cells are critical for Chlamydia clearance, but the contexts in which they are protective or not protective are unknown. Here, we aimed to characterize the importance of gamma interferon production and sensing by T cells and the effects on the immune response to C. trachomatis. Our work here helps to define the contexts in which antigen-specific T cells can be protective, which is critical to our ability to design an effective and protective vaccine against C. trachomatis.

The lignin biosynthetic pathway is highly conserved in angiosperms, yet pathway manipulations give rise to a variety of taxon-specific outcomes. Knockout of lignin-associated 4-coumarate:CoA ligases (4CLs) in herbaceous species mainly reduces guaiacyl (G) lignin and enhances cell wall saccharification. Here we show that CRISPR-knockout of 4CL1 in poplar (Populus tremula x alba) preferentially reduced syringyl (S) lignin, with negligible effects on biomass recalcitrance. Concordant with reduced S-lignin was downregulation of ferulate 5-hydroxylases (F5Hs). Lignification was largely sustained by 4CL5, a low-affinity paralog of 4CL1 typically with only minor xylem expression or activity. Levels of caffeate, the preferred substrate of 4CL5, increased in line with significant upregulation of caffeoyl shikimate esterase1. Upregulation of caffeoyl-CoA O-methyltransferase1 and downregulation of F5Hs are consistent with preferential funneling of 4CL5 products toward G-lignin biosynthesis at the expense of S-lignin. Thus, transcriptional and metabolic adaptations to 4CL1-knockout appear to have enabled 4CL5 catalysis at a level sufficient to sustain lignification. Finally, genes involved in sulfur assimilation, the glutathione-ascorbate cycle, and various antioxidant systems were upregulated in the mutants, suggesting cascading responses to perturbed thioesterification in lignin biosynthesis.

Key Points

Shih-Jung Hsu and Bo Cheng

In the presence of wind or background image motion, flies are able to maintain a constant retinal slip velocity via regulating flight speed to the extent permitted by their locomotor capacity. Here we investigated the retinal slip compensation of tethered blue-bottle flies (Calliphora vomitoria) flying semi-freely along an annular corridor in a magnetically levitated flight mill enclosed by two motorized cylindrical walls. We perturbed the flies’ retinal slip via spinning the cylindrical walls, generating bilaterally averaged retinal slip perturbations from -0.3 to 0.3 m·s^–1 (or -116.4 to 116.4 deg.·s^–1) When the perturbation was less than ~0.1 m·s^–1 (38.4 deg.·s^–1), the flies successfully compensated the perturbations and maintained a retinal slip velocity by adjusting their airspeed up to 20%. However, with greater retinal slip perturbation, the flies’ compensation became saturated, as the flies’ airspeed plateaued, indicating that they were unable to further maintain a constant retinal slip velocity. The compensation gain, i.e., the ratio of airspeed compensation and retinal slip perturbation, depended on the spatial frequency of the grating patterns, being the largest at 12 m^–1 (0.04 deg.^–1).

ABSTRACTIntroduction:Multimonth dispensing (MMD) of antiretroviral therapy (ART) is a differentiated model of care that can help overcome health system challenges and reduce the burden of HIV care on clients. Although 3-month dispensing has been the standard of care, interest has increased in extending refill intervals to 6 months. We explored client and provider experiences with MMD in Malawi as part of a cluster randomized trial evaluating 3- versus 6-month ART dispensing.Methods:Semi-structured in-depth interviews were conducted with 17 ART providers and 62 stable, adult clients with HIV on ART. Clients and providers were evenly divided by arm and were eligible for an interview if they had been participating in the study for 1 year (clients) or 6 months (providers). Questions focused on perceived challenges and benefits of the 3- or 6-month amount of ART dispensing. Interviews were transcribed, and data were coded and analyzed using constant comparison.Results:Both clients and providers reported that the larger medication supply had benefits. Clients reported decreased costs due to less frequent travel to the clinic and increased time for income-generating activities. Clients in the 6-month dispensing arm reported a greater sense of personal freedom and normalcy. Providers felt that the 6-month dispensing interval reduced their workload. They also expressed concerned about clients' challenges with ART storage at home, but clients reported no storage problems. Although providers mentioned the potential risk of clients sharing the larger medication supply with family or friends, clients emphasized the value of ART and reported only rare, short-term sharing, mostly with their spouses. Providers mentioned clients' lack of motivation to seek care for illnesses that might occur between refill appointments.Conclusions:The 6-month ART dispensing arm was particularly beneficial to clients for decreased costs, increased time for income generation, and a greater sense of normalcy. Providers' concerns about storage, sharing, and return visits to the facility did not emerge in client interviews. Further data are needed on the feasibility of implementing a large-scale program with 6-month dispensing.

Mixed lineage leukemia (MLL/KMT2A) rearrangements (MLL-r) are one of the most frequent chromosomal aberrations in acute myeloid leukemia. We evaluated the function of Meningioma 1 (MN1), a co-factor of HOXA9 and MEIS1, in human and murine MLL-rearranged leukemia by CRISPR-Cas9 mediated deletion of MN1. MN1 was required for in vivo leukemogenicity of MLL positive murine and human leukemia cells. Loss of MN1 inhibited cell cycle and proliferation, promoted apoptosis and induced differentiation of MLL-rearranged cells. Expression analysis and chromatin immunoprecipitation with sequencing from previously reported data sets demonstrated that MN1 primarily maintains active transcription of HOXA9 and HOXA10, which are critical downstream genes of MLL, and their target genes like BCL2, MCL1 and Survivin. Treatment of MLL-rearranged primary leukemia cells with anti-MN1 siRNA significantly reduced their clonogenic potential in contrast to normal CD34⁺ hematopoietic progenitor cells, suggesting a therapeutic window for MN1 targeting. In summary, our findings demonstrate that MN1 plays an essential role in MLL fusion leukemias and serve as a therapeutic target in MLL-rearranged acute myeloid leukemia.

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Read our live updates on coronavirus HERE Cornavirus: The symptoms

Follow our live coronavirus updates HERE Coronavirus: the symptoms

Follow our live coronavirus updates HERE Coronavirus: the symptoms

Read our coronavirus live updates HERE Coronavirus: The symptoms

You can donate at virginmoneygiving.com/fund/FoodforLondonNOW

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The lawyer for the woman who has been charged over the death of teenage motorcyclist Harry Dunn has opened up a dialogue with the UK Foreign Office (FCO), a source has said.

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The animal park behind Netflix hit Tiger King has official reopened its doors for business after closing due to the coronavirus outbreak.

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The Tyson Foods plant in Waterloo, Iowa, reopened Thursday after a coronavirus outbreak there. Black Hawk County Sheriff Tony Thompson says he'd support a second shutdown if the changes aren't enough.

Taylor Swift sent a care package to a registered nurse in Utah, Whitney Hilton, who just returned from New York after providing assistance at Northwell Health’s Long Island Jewish Medical Center. “I wanted to send you some presents and to let you know I am so grateful for you”, Swift began in her handwritten note, […]

The post Taylor Swift Pens A Thank You Letter To A Nurse Fighting At The Frontlines appeared first on Chart Attack.

1. Coronavirus Lockdown 3.0: Suspension of labour laws by fiat can only be an immediate-term response to the...  Firstpost
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