Orchestration of myeloid-derived suppressor cells in the tumor microenvironment by ubiquitous cellular protein TCTP released by tumor cells.

One of most challenging issues in tumor immunology is a better understanding of the dynamics in the accumulation of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TIME), as this would lead to the development of new cancer therapeutics. Here, we show that translationally controlled tumor protein (TCTP) released by dying tumor cells is an immunomodulator crucial to full-blown MDSC accumulation in the TIME. We provide evidence that extracellular TCTP mediates recruitment of the polymorphonuclear MDSC (PMN-MDSC) population in the TIME via activation of Toll-like receptor-2. As further proof of principle, we show that inhibition of TCTP suppresses PMN-MDSC accumulation and tumor growth. In human cancers, we find an elevation of TCTP and an inverse correlation of TCTP gene dosage with antitumor immune signatures and clinical prognosis. This study reveals the hitherto poorly understood mechanism of the MDSC dynamics in the TIME, offering a new rationale for cancer immunotherapy.

Fruitless recruits two antagonistic chromatin factors to establish single-neuron sexual dimorphism.

The Drosophila fruitless (fru) gene encodes a set of putative transcription factors that promote male sexual behavior by controlling the development of sexually dimorphic neuronal circuitry. However, the mechanism whereby fru establishes the sexual fate of neurons remains enigmatic. Here, we show that Fru forms a complex with the transcriptional cofactor Bonus (Bon), which, in turn, recruits either of two chromatin regulators, Histone deacetylase 1 (HDAC1), which masculinizes individual sexually dimorphic neurons, or Heterochromatin protein 1a (HP1a), which demasculinizes them. Manipulations of HDAC1 or HP1a expression change the proportion of male-typical neurons and female-typical neurons rather than producing neurons with intersexual characteristics, indicating that on a single neuron level, this sexual switch operates in an all-or-none manner.

Structural colour using organized microfibrillation in glassy polymer films.

The formation of microscopic cavities and microfibrils at stress hotspots in polymers is typically undesirable and is a contributor to material failure. This type of stress crazing is accelerated by solvents that are typically weak enough not to dissolve the polymer substantially, but which permeate and plasticize the polymer to facilitate the cavity and microfibril formation process1-3. Here we show that microfibril and cavity formation in polymer films can be controlled and harnessed using standing-wave optics to design a periodic stress field within the film4. We can then develop the periodic stress field with a weak solvent to create alternating layers of cavity and microfibril-filled polymers, in a process that we call organized stress microfibrillation. These multi-layered porous structures show structural colour across the full visible spectrum, and the colour can be tuned by varying the temperature and solvent conditions under which the films are developed. By further use of standard lithographic and masking tools, the organized stress microfibrillation process becomes an inkless, large-scale colour printing process generating images at resolutions of up to 14,000 dots per inch on a number of flexible and transparent formats5,6.

Engineering of a Low-Entropy Quantum Simulator for Strongly Correlated Electrons Using Cold Atoms with SU(N)-Symmetric Interactions.

An advanced cooling scheme, incorporating entropy engineering, is vital for isolated artificial quantum systems designed to emulate the low-temperature physics of strongly correlated electron systems. This study theoretically demonstrates a cooling method employing multicomponent Fermi gases with SU(N)-symmetric interactions, focusing on the case of ^{173}Yb atoms in a two-dimensional optical lattice. Adiabatically introducing a nonuniform state-selective laser gives rise to two distinct subsystems: a central low-entropy region, exclusively composed of two specific spin components, acts as a quantum simulator for strongly correlated electron systems, while the surrounding N-component mixture retains a significant portion of the entropy of the system. The total particle numbers for each component are good quantum numbers, creating a sharp boundary for the two-component region. The cooling efficiency is assessed through extensive finite-temperature Lanczos calculations. The results lay the foundation for quantum simulations of two-dimensional systems of Hubbard or Heisenberg type, offering crucial insights into intriguing low-temperature phenomena in condensed-matter physics.

Manganese-Catalyzed 5-Endo-trig Oxygenative Cyclization of α,ß-Unsaturated Oximes under Air and Ambient Conditions for the Synthesis of 4,5-Dihydroisoxazoles.

The stereoselective 5-endo-trig oxygenative cyclization of α,ß-unsaturated oximes was achieved using molecular oxygen (O2) and a manganese catalyst. Several 4-hydroxy-4,5-dihydroisoxazoles were obtained in high yields by directly incorporating O2 from the atmosphere (eliminating the necessity for a pure oxygen environment) and using an unprecedentedly low loading of Mn(acac)3 (as little as 0.020 mol %) without additional additives. Because of its desirable features, such as operational simplicity, inexpensive catalyst, mild reaction conditions (open flask conditions at room temperature), and broad substrate compatibility, this novel reaction provides an attractive synthetic approach to producing 4-hydroxy-4,5-dihydroisoxazoles.

New Diagnostic Modality Combining Mass Spectrometry and Machine Learning for the Discrimination of Malignant Intraductal Papillary Mucinous Neoplasms.

BACKGROUND: An intraductal papillary mucinous neoplasm (IPMN) is a pancreatic tumor with malignant potential. Although we anticipate a sensitive method to diagnose the malignant conversion of IPMN, an effective strategy has not yet been established. The combination of probe electrospray ionization-mass spectrometry (PESI-MS) and machine learning provides a promising solution for this purpose. METHODS: We prospectively analyzed 42 serum samples obtained from IPMN patients who underwent pancreatic resection between 2020 and 2021. Based on the postoperative pathological diagnosis, patients were classified into two groups: IPMN-low grade dysplasia (n = 17) and advanced-IPMN (n = 25). Serum samples were analyzed by PESI-MS, and the obtained mass spectral data were converted into continuous variables. These variables were used to discriminate advanced-IPMN from IPMN-low grade dysplasia by partial least square regression or support vector machine analysis. The areas under receiver operating characteristics curves were obtained to visualize the difference between the two groups. RESULTS: Partial least square regression successfully discriminated the two disease classes. From another standpoint, we selected 130 parameters from the entire dataset by PESI-MS, which were fed into the support vector machine. The diagnostic accuracy was 88.1%, and the area under the receiver operating characteristics curve was 0.924 by this method. Approximately 10 min were required to perform each method. CONCLUSION: PESI-MS combined with machine learning is an easy-to-use tool with the advantage of rapid on-site analysis. Here, we show the great potential of our system to diagnose the malignant conversion of IPMN, which would be a promising diagnostic tool in clinical settings.

Characterization of RNF43 frameshift mutations that drive Wnt ligand- and R-spondin-dependent colon cancer.

Loss-of-function mutations in RNF43 induce activation of Wnt ligand-dependent Wnt/ß-catenin signaling through stabilization of the Frizzled receptor, which is often found in microsatellite instability (MSI)-type colorectal cancer (CRC) that develops from sessile serrated adenomas. However, the mechanism underlying how RNF43 mutations promote tumorigenesis remains poorly understood. In this study, we established nine human CRC-derived organoids and found that three organoid lines carried RNF43 frameshift mutations associated with MSI-high and BRAFV600E mutations, suggesting that these CRCs developed through the serrated pathway. RNF43 frameshift mutant organoids required both Wnt ligands and R-spondin for proliferation, indicating that suppression of ZNRF3 and retained RNF43 function by R-spondin are required to achieve an indispensable level of Wnt activation for tumorigenesis. However, active ß-catenin levels in RNF43-mutant organoids were lower than those in APC two-hit mutant CRC, suggesting a lower threshold for Wnt activation in CRC that developed through the serrated pathway. Interestingly, transplantation of RNF43-mutant organoids with intestinal myofibroblasts accelerated the ß-catenin nuclear accumulation and proliferation of xenograft tumors, indicating a key role of stromal cells in the promotion of the malignant phenotype of RNF43-mutant CRC cells. Sequencing of subcloned organoid cell-expressed transcripts revealed that two organoid lines carried monoallelic RNF43 cis-mutations, with two RNF43 frameshift mutations introduced in the same allele and the wild-type RNF43 allele remaining, while the other organoid line carried two-hit biallelic RNF43 trans-mutations. These results suggest that heterozygous RNF43 frameshift mutations contribute to CRC development via the serrated pathway; however, a second-hit RNF43 mutation may be advantageous in tumorigenesis compared with a single-hit mutation through further activation of Wnt signaling. Finally, treatment with the PORCN inhibitor significantly suppressed RNF43-mutant cell-derived PDX tumor development. These results suggest a novel mechanism underlying RNF43 mutation-associated CRC development and the therapeutic potential of Wnt ligand inhibition against RNF43-mutant CRC. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Angiographic evaluation of the distance from the top of the jugular bulb to the inferior petrosal sinus-internal jugular vein junction: simple classification and identification method for the orifice of the non-visualized inferior petrosal sinus during neuroendovascular surgery.

BACKGROUND: The inferior petrosal sinus (IPS) is the transvenous access route for neurointerventional surgery that is occasionally undetectable on digital subtraction angiography (DSA) because of blockage by a clot or collapse. This study was aimed at analyzing the distance from the jugular bulb (JB) to the IPS-internal jugular vein (IJV) junction and proposing a new anatomical classification system for the IPS-IJV junction to identify the non-visualized IPS orifice. METHODS: DSA of 708 IPSs of 375 consecutive patients were retrospectively investigated to calculate the distance from the top of the JB to the IPS-IJV junction, and a simple classification system based on this distance was proposed. RESULTS: The median distance from the top of the JB to the IPS-IJV junction was 20.8 ± 14.7 mm. Based on the lower (10.9 mm) and upper (31.1 mm) quartiles, IPS-IJV junction variants were: type I, 0-10 mm (22.3%); type II, 11-30 mm (45.8%); type III, > 31 mm (23.9%); and type IV, no connection to the IJV (8.0%). Bilateral distances showed a positive interrelationship, with a correlation coefficient of 0.86. The bilateral symmetry type (visualized IPSs bilaterally) according to our classification occurred in 267 of 300 (89.0%) patients. CONCLUSIONS: In this study, the IPS-IJV junction was located far from the JB (types II and III), with a higher probability (69.6%). This distance and the four-type classification demonstrated high degrees of homology with the contralateral side. These results would be useful for identifying the non-visualized IPS orifice.

Analysis of contributory factors to incidents related to medication assistance for residents taking medicines in residential care homes for the elderly: a qualitative interview survey with care home staff.

BACKGROUND: In Japan, staff who are not doctors or nurses can assist the elderly in residential care facilities to take their pre-packaged medicines. Therefore, there is a potential risk of incidents specific to staffs. The aim of this study was to clarify the causes of incidents related to medication assistance by staff in residential care facilities. METHOD: Semi-structured interviews with staff involved in medication incidents in long-term care facilities, focusing on how and why each incident happened, were conducted. The interview covered basic information about the subject and resident, the circumstances under which the incident had occurred, contributing factors, and countermeasures put in place. Verbatim transcripts of the interviews were prepared. Based on thematic analysis, codes and themes were created. RESULTS: Twelve subjects participated in this study. All subjects were staffs (not doctors or nurses) in long-term care facilities. All incidents covered in this study were incidents in which the wrong resident was given the medication. The incidents arose because of "not following procedures", such as lack of "self-check of residents' faces/residents' names/residents' medicine envelopes" or "double-check with other staff" or "using a device for medication intake". Contributory factors were grouped into four categories: individual resident factor items such as "decreased ability to understand their medication" or "refusal to take medicines", individual staff factor items such as "lack of knowledge related to medication" or "mental burden" or "experience in medication assistance", team factor items such as "failure to communicate with other staff", work environment factor items such as "presence of other residents" or "other work besides medication assistance" or "not enough time" or "little understanding of fostering a safety culture at the facility". CONCLUSION: This study identified four categories of contributory factors that may lead to incidents during medication assistance by caregivers for residents of care homes. These findings should be helpful for risk management in residential care facilities where staff usually provide medication assistance. Separation of meal times and medication assistance, and professional review to stagger the timing of administration of residents' medication may be effective in reducing incidents.

Calmodulin-binding transcription factor shapes the male courtship song in Drosophila.

Males of the Drosophila melanogaster mutant croaker (cro) generate a polycyclic pulse song dissimilar to the monocyclic songs typical of wild-type males during courtship. However, cro has not been molecularly mapped to any gene in the genome. We demonstrate that cro is a mutation in the gene encoding the Calmodulin-binding transcription factor (Camta) by genetic complementation tests with chromosomal deficiencies, molecular cloning of genomic fragments that flank the cro-mutagenic P-insertion, and phenotypic rescue of the cro mutant phenotype by Camta+-encoding cDNA as well as a BAC clone containing the gene for Camta. We further show that knockdown of the Camta-encoding gene phenocopies cro mutant songs when targeted to a subset of fruitless-positive neurons that include the mcALa and AL1 clusters in the brain. cro-GAL4 and an anti-Camta antibody labeled a large number of brain neurons including mcALa. We conclude that the Camta-encoding gene represents the cro locus, which has been implicated in a species-specific difference in courtship songs between D. sechellia and simulans.

CRISPR-Cas9-mediated gene knockout in intestinal tumor organoids provides functional validation for colorectal cancer driver genes.

Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide. Several genome sequencing studies have provided comprehensive CRC genomic datasets. Likewise, in our previous study, we performed genome-wide Sleeping Beauty transposon-based mutagenesis screening in mice and provided comprehensive datasets of candidate CRC driver genes. However, functional validation for most candidate CRC driver genes, which were commonly identified from both human and mice, has not been performed. Here, we describe a platform for functionally validating CRC driver genes that utilizes CRISPR-Cas9 in mouse intestinal tumor organoids and human CRC-derived organoids in xenograft mouse models. We used genetically defined benign tumor-derived organoids carrying 2 frequent gene mutations (Apc and Kras mutations), which act in the early stage of CRC development, so that we could clearly evaluate the tumorigenic ability of the mutation in a single gene. These studies showed that Acvr1b, Acvr2a, and Arid2 could function as tumor suppressor genes (TSGs) in CRC and uncovered a role for Trp53 in tumor metastasis. We also showed that co-occurrent mutations in receptors for activin and transforming growth factor-ß (TGF-ß) synergistically promote tumorigenesis, and shed light on the role of activin receptors in CRC. This experimental system can also be applied to mouse intestinal organoids carrying other sensitizing mutations as well as organoids derived from other organs, which could further contribute to identification of novel cancer driver genes and new drug targets.

Inflammatory and mitogenic signals drive interleukin 23 subunit alpha (IL23A) secretion independent of IL12B in intestinal epithelial cells.

The heterodimeric cytokine interleukin-23 (IL-23 or IL23A/IL12B) is produced by dendritic cells and macrophages and promotes the proinflammatory and regenerative activities of T helper 17 (Th17) and innate lymphoid cells. A recent study has reported that IL-23 is also secreted by lung adenoma cells and generates an inflammatory and immune-suppressed stroma. Here, we observed that proinflammatory tumor necrosis factor (TNF)/NF-κB and mitogen-activated protein kinase (MAPK) signaling strongly induce IL23A expression in intestinal epithelial cells. Moreover, we identified a strong crosstalk between the NF-κB and MAPK/ERK kinase (MEK) pathways, involving the formation of a transcriptional enhancer complex consisting of proto-oncogene c-Jun (c-Jun), RELA proto-oncogene NF-κB subunit (RelA), RUNX family transcription factor 1 (RUNX1), and RUNX3. Collectively, these proteins induced IL23A secretion, confirmed by immunoprecipitation of endogenous IL23A from activated human colorectal cancer (CRC) cell culture supernatants. Interestingly, IL23A was likely secreted in a noncanonical form, as it was not detected by an ELISA specific for heterodimeric IL-23 likely because IL12B expression is absent in CRC cells. Given recent evidence that IL23A promotes tumor formation, we evaluated the efficacy of MAPK/NF-κB inhibitors in attenuating IL23A expression and found that the MEK inhibitor trametinib and BAY 11-7082 (an IKKα/IκB inhibitor) effectively inhibited IL23A in a subset of human CRC lines with mutant KRAS or BRAFV600E mutations. Together, these results indicate that proinflammatory and mitogenic signals dynamically regulate IL23A in epithelial cells. They further reveal its secretion in a noncanonical form independent of IL12B and that small-molecule inhibitors can attenuate IL23A secretion.

Short-term safety of adjuvant chemoradiotherapy after local resection for patients with high-risk submucosal invasive rectal cancer: a single-arm, multicenter phase II trial.

BACKGROUND: Surgery is recommended for patients with high-risk submucosal invasive rectal cancer (SM-RC) after local resection but affects the quality of life due to stoma placement or impaired anal function; therefore, alternative treatment approaches are needed to prevent local metastasis. The purpose of this study was to assess the short-term safety of adjuvant chemoradiotherapy with capecitabine in patients with high-risk submucosal invasive rectal cancer after local resection. METHODS: This single-arm, multicenter, phase II trial included patients undergoing local resection for high-risk submucosal invasive rectal cancer within 12 weeks prior to enrollment. High-risk submucosal invasive rectal cancer was defined as the presence of at least one of the following factors: poor differentiation of adenocarcinoma, submucosal invasion depth > 1 mm, presence of lymphovascular invasion and grade-2 or -3 tumour budding. Protocol treatment comprised 45.0 Gy radiotherapy with conventional fractionation and 1650 mg/m2 capecitabine given twice daily until radiotherapy completion. The primary endpoint was treatment completion rate with an expected rate of 95% and a threshold of 80%. RESULTS: Twenty-nine patients from six institutions were enrolled between May 2015 and February 2018. One patient was ineligible. Twenty-three patients completed treatment, with a completion rate of 82% (80% confidence interval, 69-91%); the remaining five patients completed treatment with protocol deviation. The median relative dose intensity of capecitabine was 100% (range, 58-100%). Common adverse events included radiation dermatitis (54%), anal pain (39%) and anal mucositis (29%). No grade-3 or higher adverse events were reported. CONCLUSIONS: Adjuvant chemoradiotherapy using capecitabine demonstrated acceptable short-term safety profiles in patients with high-risk submucosal invasive rectal cancer after local resection.

Acetaminophen Exerts an Analgesic Effect on Muscular Hyperalgesia in Repeated Cold-Stressed Rats through the Enhancement of the Descending Pain Inhibitory System Involving Spinal 5-HT3 and Noradrenergic α2 Receptors.

Musculoskeletal and psychological complaints have increased with the widespread use of visual display terminals, and musculoskeletal pain is known to be closely related to stress. One method of experimentally inducing persistent muscle pain is repeated cold stress (RCS), and animals exposed to such stress exhibit a dysfunction in the descending pain inhibitory system. Acetaminophen (N-acetyl-p-aminophenol; APAP) is widely used to relieve several types of pain, including musculoskeletal pain, and is available as an OTC drug. However, the mechanism underlying its analgesic action has not yet been fully elucidated. In this study, we compared the analgesic effect of APAP on RCS-induced muscular hyperalgesia with those of other analgesics to identify its mechanism of action. The daily oral administration of APAP significantly suppressed the decrease in the mechanical withdrawal threshold caused by RCS, similar to the results for neurotropin but not for the cyclooxygenase inhibitor ibuprofen (IBP). Moreover, the intrathecal administration of antagonists of the 5-hydroxytryptamine (5-HT)3 receptor or α2-adrenoceptor significantly abolished the analgesic effect of APAP but not of IBP. These results suggest that the analgesic effect of APAP on RCS-induced muscular pain might be exerted due to the activation of the descending pathways involving the spinal 5-HT3 receptor or α2-adrenoceptor.

Genetic dissection of stress-induced reproductive arrest in Drosophila melanogaster females.

By genetic manipulations, we study the roles played by insulin-producing cells (IPCs) in the brain and their target, the corpora allata (CA), for reproductive dormancy in female Drosophila melanogaster, which is induced by exposing them to a combination of low temperature (11°C), short-day photoperiod (10L:14D) and starvation (water only) for 7 days immediately after eclosion (dormancy-inducing conditions). Artificial inactivation of IPCs promotes, whereas artificial activation impedes, the induction of reproductive dormancy. A transcriptional reporter assay reveals that the IPC activity is reduced when the female flies are exposed to dormancy-inducing conditions. The photoperiod sensitivity of reproductive dormancy is lost in pigment-dispersing factor (pdf), but not cry, mutants, suggesting that light input to IPCs is mediated by pdf-expressing neurons. Genetic manipulations to upregulate and downregulate insulin signaling in the CA, a pair of endocrine organs that synthesize the juvenile hormone (JH), decrease and increase the incidence of reproductive dormancy, respectively. These results demonstrate that the IPC-CA axis constitutes a key regulatory pathway for reproductive dormancy.

[Anterior Cranial Fossa Dural Arteriovenous Fistula with Specific Drainage Route Presenting Aphasia after Head Trauma:A Case Report].

In this case report, we describe a rare case of anterior cranial fossa dural arteriovenous fistula(ACF-dAVF)that had drained into the fronto-basal vein and refluxed to the superficial middle cerebral vein(SMCV). A 45-year-old man presented with aphasia and swelling of the left eye after head trauma. MRI detected a flow void in the left frontal basal area, and digital subtraction angiography revealed ACF-dAVF, which was fed from the ophthalmic arteries on both sides and had a shunt point within the left front basal dura. It drained into the left front basal vein and refluxed to the left SMCV via the cavernous sinus. Aphasia occurred due to the reflux of the SMCV. We treated the patient with transcatheter arterial embolization(TAE)by injecting n-butyl-2-cyanoacrylate(NBCA)into the shunt point. Immediately after TAE, the aphasia and swelling of the left eye of the patient improved. Cases of ACF-dAVF that drain not into the frontal cortical veins but into the fronto-basal vein and SMCV are relatively rare. As ACF-dAVF occasionally causes frontal symptoms such as aphasia, we should carefully investigate such patients and consider the presence of ACF-dAVF.

Intracellular claudin-1 at the invasive front of tongue squamous cell carcinoma is associated with lymph node metastasis.

Claudins are the major component of tight junctions, which form a primary barrier to paracellular diffusion and maintain cell polarity in normal epithelia and endothelia. In cancer cells, claudins play additional roles besides serving as components of the tight junctions, and participate in anoikis or invasion. Among the claudin family proteins, claudin-1 has the most promising potential, both diagnostically and prognostically, in many types of cancers, including oral, gastric, liver, and colon cancers. However, conflicting results have been reported in relation to the degree of claudin-1 expression and the prognosis, suggesting that the expression level of claudin-1 alone is not sufficient to analyze the relationship between claudin-1 and cancer progression. As endocytic trafficking of claudin-1 has been reported in several epithelial cell types in vitro, we aimed to determine whether intracellular localization of claudin-1 is the missing aspect between claudin-1 and cancer. We investigated the expression of claudin-1 in 83 tongue squamous cell carcinoma (TSCC) pathological specimens. Although the expression level of claudin-1 based on immunohistochemistry was not associated with TSCC progression, within the high claudin-1 expression group, the incidence of intracellular localization of claudin-1 was correlated with cervical lymph node metastasis. In an in vitro experiment, claudin-1 was constitutively internalized in TSCC-derived cells. Motility of TSCC-derived cells was increased by deficiency of claudin-1, suggesting that the decrease in cell-surface claudin-1 promoted the cell migration. Therefore, intracellular localization of claudin-1 at the invasion front may represent a promising diagnostic marker of TSCC.

Quantum and Thermal Phase Transitions of the Triangular SU(3) Heisenberg Model under Magnetic Fields.

We study the quantum and thermal phase transition phenomena of the SU(3) Heisenberg model on triangular lattice in the presence of magnetic fields. Performing a scaling analysis on large-size cluster mean-field calculations endowed with a density-matrix renormalization-group solver, we reveal the quantum phases selected by quantum fluctuations from the massively degenerate classical ground-state manifold. The magnetization process up to saturation reflects three different magnetic phases. The low- and high-field phases have strong nematic nature, and especially the latter is found only via a nontrivial reconstruction of symmetry generators from the standard spin and quadrupolar description. We also perform a semiclassical Monte Carlo simulation to show that thermal fluctuations prefer the same three phases as well. Moreover, we find that exotic topological phase transitions driven by the binding-unbinding of fractional (half-)vortices take place, due to the nematicity of the low- and high-field phases. Possible experimental realization with alkaline-earth-like cold atoms is also discussed.

Baculovirus-Induced Fast-Acting Innate Immunity Kills Liver-Stage Plasmodium.

Baculovirus (BV), an enveloped insect virus with a circular dsDNA genome, possesses unique characteristics that induce strong innate immune responses in mammalian cells. In this study, we show that BV administration in BALB/c mice not only provides complete protection against a subsequent Plasmodium berghei sporozoite infection for up to 7 d after the injection but also eliminates existing liver-stage parasites completely. The elimination of sporozoites by BV was superior to that by primaquine, and this effect occurred in a TLR9-independent manner. At 6 h after BV administration, IFN-α and IFN-γ were robustly produced in the serum, and RNA transcripts of IFN-stimulated genes were markedly upregulated in the liver compared with control mice. The in vivo passive transfer of serum after BV administration effectively eliminated liver-stage parasites, and IFN-α neutralization abolished this effect, indicating that the BV liver-stage parasite-killing mechanism is downstream of the type I IFN signaling pathway. These findings provide evidence that BV-induced, fast-acting innate immunity completely kills liver-stage parasites and, thus, may lead to new malaria drug and vaccine strategies.

Heat trapping in a nano-layered microenvironment: estimation of temperature by thermal sensing molecules.

We have previously found reversible photo-induced expansion and contraction of organic/inorganic clay hybrids, and even sliding of niobate nano-sheets at the macroscopic level of organic/inorganic niobate hybrids, induced by the molecular photo-isomerization of the polyfluoroalkylated azobenzene derivative (C3F-Azo-C6H) intercalated within the interlayer, which is viewed as an artificial muscle model unit. Based on systematic investigations of the steady state photo-isomerization and transient behavior of the reaction, we comprehended that the phenomena is caused by trapping of excess energy liberated during the isomerization, as well as the relaxation processes upon excitation of azobenzene chromophores in the interlayers of the hybrid. In this paper, quantitative estimation of transient 'heat' trapped in various microenvironments has been studied by each co-intercalation of temperature sensing dye molecules - rhodamine B (RhB) or tris(bipyridine)ruthenium(ii) chloride (Rubpy) with C3F-Azo-C6H within clay (SSA) nano-layers. The amount of dye molecules co-intercalated was kept to trace amounts that did not alter the bi-layered structure of the hybrid. The temperature of the microenvironment surrounding the probe molecules was estimated from the emission lifetime analysis. The evidently reduced emission lifetimes in C3F-Azo-C6H/SSA and C3H-Azo-C6H/SSA hybrids in the film state, indicated the elevation of temperature of the microenvironment upon excitation of the chromophores, which demonstrated our previous hypothesis rationalizing that the high reactivity of isomerization in the hybrid film state is caused by heat trapping via multi-step dissipation of the excess energy. With the hybrid of a hydrocarbon analogue (C3H-Azo-C6H), a distinct difference in temperature gradient was found to show the crucial role of the perfluoroalkyl chain of the surfactant that traps the excess energy to retard its dissipation leading to three-dimensional morphological motion.