Using smartphone user mobility to unveil actual travel time to healthcare: An example of mental health facilities.

Travel time to health facilities is one of the most important factors in evaluating health disparity. Previous extensive research has primarily leveraged the driving time to the nearest health facility to gauge travel time. However, such ideal travel time (ITT) may not accurately represent real individual travel time to health services and is often underestimated.

ATG5-regulated CCL2/MCP-1 production in myeloid cells selectively modulates anti-malarial CD4 Th1 responses.

Parasite-specific CD4 Th1 cell responses are the predominant immune effector for controlling malaria infection; however, the underlying regulatory mechanisms remain largely unknown. This study demonstrated that ATG5 deficiency in myeloid cells can significantly inhibit the growth of rodent blood-stage malarial parasites by selectively enhancing parasite-specific CD4 Th1 cell responses. This effect was independent of ATG5-mediated canonical and non-canonical autophagy.

Malaria oocysts require circumsporozoite protein to evade mosquito immunity.

Malaria parasites are less vulnerable to mosquito immune responses once ookinetes transform into oocysts, facilitating parasite development in the mosquito. However, the underlying mechanisms of oocyst resistance to mosquito defenses remain unclear. Here, we show that circumsporozoite protein (CSP) is required for rodent malaria oocysts to avoid mosquito defenses.

The Dynamic Change of Immune Responses Between Acute and Recurrence Stages of Rodent Malaria Infection.

Malaria infections are persistent as frequent recrudescence of the disease may occur following the acute infection stage, but the different immune responses that control the acute and recrudescence stages are still largely unknown. Using single-cell RNA sequencing (scRNA-seq), we showed that the number of Th1 and plasma cells in the spleen was significantly reduced during the recurrence stage compared to the acute stage of () infection. Additionally, the ability of both CD4 T cell responses and B cells to control recurrence was significantly reduced compared to their roles in the control of acute infection.

ATG Ubiquitination Is Required for Circumsporozoite Protein to Subvert Host Innate Immunity Against Rodent Malaria Liver Stage.

Although exo-erythrocytic forms (EEFs) of liver stage malaria parasite in the parasitophorous vacuole (PV) are encountered with robust host innate immunity, EEFs can still survive and successfully complete the infection of hepatocytes, and the underlying mechanism is largely unknown. Here, we showed that sporozoite circumsporozoite protein (CSP) translocated from the parasitophorous vacuole into the hepatocyte cytoplasm significantly mediated the resistance to the killing of EEFs by interferon-gamma (IFN-γ). Attenuation of IFN-γ-mediated killing of EEFs by CSP was dependent on its ability to reduce the levels of autophagy-related genes (ATGs) in hepatocytes.

The dynamic landscape of parasitemia dependent intestinal microbiota shifting and the correlated gut transcriptome during Plasmodium yoelii infection.

Malaria, caused by Plasmodium, is a global life-threatening infectious disease. However, the dynamic interactions between intestinal microbiota and host immunity during the infections are still unclear. Here, we investigated the change of intestinal microbiome and transcriptome during Plasmodium yoelii infection in mice.

Drug Repurposing of Quisinostat to Discover Novel HDAC1 Inhibitors with Enhanced Triple-Stage Antimalarial Activity and Improved Safety.

Our previous work found that the clinical histone deacetylase (HDAC) inhibitor quisinostat exhibited a significant antimalarial effect but with severe toxicity. In this work, 35 novel derivatives were designed and synthesized based on quisinostat as the lead compound, and their in vitro antimalarial activities and cytotoxicities were systematically evaluated. Among them, showed potent inhibition against both wild-type and multidrug-resistant parasite strains and displayed a significant in vivo killing effect against all life cycles of parasites, including the blood stage, liver stage, and gametocyte stage, indicating its potential for the simultaneous treatment, chemoprevention, and blockage of malaria transmission.

Whole-Killed Blood-Stage Vaccine: Is It Worthwhile to Further Develop It to Control Malaria?

Major challenges have been encountered regarding the development of highly efficient subunit malaria vaccines, and so whole-parasite vaccines have regained attention in recent years. The whole-killed blood-stage vaccine (WKV) is advantageous as it can be easily manufactured and efficiently induced protective immunity against a blood-stage challenge, as well as inducing cross-stage protection against both the liver and sexual-stages. However, it necessitates a high dose of parasitized red blood cell (pRBC) lysate for immunization, and this raises concerns regarding its safety and low immunogenicity.

Discovery of Novel HDAC1 Inhibitors with Dual-Stage Antimalarial Potency and Improved Safety Based on the Clinical Anticancer Drug Candidate Quisinostat.

Previously, we identified the clinical anticancer drug candidate quisinostat as a novel and potent antimalarial lead compound. To further enhance the antimalarial effect and improve safety, 31 novel spirocyclic hydroxamic acid derivatives were synthesized based on the structure of quisinostat, and their antimalarial activities and cytotoxicity were evaluated. Among them, compound displayed broad potency against several multiresistant malarial parasites, especially two artemisinin-resistant clinical isolates.

A novel multistage antiplasmodial inhibitor targeting Plasmodium falciparum histone deacetylase 1.

Although artemisinin combination therapies have succeeded in reducing the global burden of malaria, multidrug resistance of the deadliest malaria parasite, Plasmodium falciparum, is emerging worldwide. Innovative antimalarial drugs that kill all life-cycle stages of malaria parasites are urgently needed. Here, we report the discovery of the compound JX21108 with broad antiplasmodial activity against multiple life-cycle stages of malaria parasites.

Blood-stage malaria parasites manipulate host innate immune responses through the induction of sFGL2.

Malaria parasites suppress host immune responses to facilitate their survival, but the underlying mechanism remains elusive. Here, we found that blood-stage malaria parasites predominantly induced CD4Foxp3CD25 regulatory T cells to release soluble fibrinogen-like protein 2 (sFGL2), which substantially enhanced the infection. This was attributed to the capacity of sFGL2 to inhibit macrophages from releasing monocyte chemoattractant protein-1 (MCP-1) and to sequentially reduce the recruitment of natural killer/natural killer T cells to the spleen and the production of interferon-γ.

Improving the immunogenicity and protective efficacy of a whole-killed malaria blood-stage vaccine by chloroquine.

A whole-killed malaria blood-stage vaccine (WKV) is promising in reducing the morbidity and mortality of malaria patients, but its efficacy needs to be improved. We found that the antimalarial drug chloroquine could augment the protective efficacy of the WKV of Plasmodium yoelii. The direct antimalarial effect of chloroquine on parasites during immunization could be excluded, as the administration of chloroquine or chloroquine plus alum every two weeks had a slight effect on parasitemia, and an immunization with NP-KLH (4-hydroxy-3-nitrophenylacetyl Keyhole Limpet Hemocyanin) plus chloroquine could significantly promote the generation of NP-specific antibodies.

PD-1 deficiency promotes TFH cells expansion in ITV-immunized mice by upregulating cytokines secretion.

Background: T follicular helper (TFH) cells are fundamental for the development of humoral immunity. In our previous study, we found that PD-1 deficiency substantially promoted the expansion of Plasmodium-specific TFH cells and enhanced the humoral immunity of ITV (infection treatment vaccine)-immunized mice. However, the underlying mechanism by which PD-1 signaling modulates TFH cells activation remains unclear.

Whole-Killed Blood-Stage Vaccine-Induced Immunity Suppresses the Development of Malaria Parasites in Mosquitoes.

As a malaria transmission-blocking vaccine alone does not confer a direct benefit to the recipient, it is necessary to develop a vaccine that not only blocks malaria transmission but also protects vaccinated individuals. In this study we observed that a whole-killed blood-stage vaccine (WKV) not only conferred protection against the blood-stage challenge but also markedly inhibited the transmission of different strains of the malaria parasite. Although the parasitemia is much lower in WKV-immunized mice challenged with malaria parasites, the gametocytemia is comparable between control and immunized mice during the early stages of infection.

The rodent malaria liver stage survives in the rapamycin-induced autophagosome of infected Hepa1-6 cells.

It has been reported that non-selective autophagy of infected hepatocytes could facilitate the development of malaria in the liver stage, but the fate of parasites following selective autophagy of infected hepatocytes is still not very clear. Here, we confirmed that sporozoite infection can induce a selective autophagy-like process targeting EEFs (exo-erythrocytic forms) in Hepa1-6. Rapamycin treatment greatly enhanced this process in EEFs and non-selective autophagy of infected Hepa1-6 cells and enhanced the development of the malaria liver stage in vivo.

Establishment of a murine model of cerebral malaria in KunMing mice infected with Plasmodium berghei ANKA.

Malaria remains one of the most devastating diseases. Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection resulting in high mortality and morbidity worldwide. Analysis of precise mechanisms of CM in humans is difficult for ethical reasons and animal models of CM have been employed to study malaria pathogenesis.

The TLR2 is activated by sporozoites and suppresses intrahepatic rodent malaria parasite development.

TLRs (Toll-like receptors) play an important role in the initiation of innate immune responses against invading microorganisms. Although several TLRs have been reported to be involved in the innate immune response against the blood-stage of malaria parasites, the role of TLRs in the development of the pre-erythrocytic stage is still largely unknown. Here, we found that sporozoite and its lysate could significantly activate the TLR2, and induce macrophages to release proinflammatory cytokines, including IL-6, MCP-1 and TNF-α, in a TLR2-dependent manner.

PD-1 deficiency enhances humoral immunity of malaria infection treatment vaccine.

Malaria infection treatment vaccine (ITV) is a promising strategy to induce homologous and heterologous protective immunity against the blood stage of the parasite. However, the underlying mechanism of protection remains largely unknown. Here, we found that a malaria-specific antibody (Ab) could mediate the protective immunity of ITV-immunized mice.

Aspects of dissipation for compressible fluids and kinetic theory.

There are several types of dissipation--the viscosity and heat conductivity, the nonlinearity and the coupling of distinct characteristics--that can occur in the system of conservation laws. In addition to these corresponding types of dissipation, there are other consequences of the H-theorem and the boundary dissipative effects for the kinetic theory. We discuss these issues and raise questions.

An essential role for C5aR signaling in the optimal induction of a malaria-specific CD4+ T cell response by a whole-killed blood-stage vaccine.

The protective immunity induced by the whole-killed parasite vaccine against malarial blood-stage infection is dependent on the CD4(+) T cell response. However, the mechanism underlying this robust CD4(+) T cell response elicited by the whole-killed parasite vaccine is still largely unknown. In this study, we observe that immunization with Plasmodium yoelii-parasitized RBC lysate activates complement C5 and generates C5a.

Divergent roles of amino acid residues inside and outside the BB loop affect human Toll-like receptor (TLR)2/2, TLR2/1 and TLR2/6 responsiveness.

TLR2 specifically recognizes a wide range of ligands by homodimerizing or heterodimerizing with TLR1 or TLR6. However, the molecular basis of the specific signalling transduction induced by TLR2 homodimerization or heterodimerization with TLR1 or TLR6 is largely unknown. In this study, we found three amino acid residues, two (663L and 688N) outside and one (681P) inside the BB loop, which were conserved in all of the TLRs, except for the TLR3 toll/IL-1R(TIR) domain.

The Plasmodium circumsporozoite protein, a novel NF-κB inhibitor, suppresses the growth of SW480.

The blocking of NF-κB activation is a promising strategy for the treatment of colorectal cancer. The circumsporozoite protein (CSP), a key component of the sporozoite stage of the malaria parasite, was recently reported to block NF-κB activation in hepatocytes. Thus, we investigated the effect of the CSP on the growth of the human colon cancer cell line, SW480.

[Immunopathological mechanism of cerebral malaria].

Cerebral malaria is a severe complication of malaria. Early studies suggest that cerebral malaria is related to cytoadherence of parasitized red blood cells to the microvessel endothelium of brain. However, more and more evidence supported that the cause of cerebral malaria is uncontrolled inflammatory cytokines and infiltration of lymphocytes in brain microvessel.