In vitro production of infectious Plasmodium falciparum sporozoites.

An effective vaccine is needed for the prevention and elimination of malaria. The only immunogens that have been shown to have a protective efficacy of more than 90% against human malaria are Plasmodium falciparum (Pf) sporozoites (PfSPZ) manufactured in mosquitoes (mPfSPZ)1-7. The ability to produce PfSPZ in vitro (iPfSPZ) without mosquitoes would substantially enhance the production of PfSPZ vaccines and mosquito-stage malaria research, but this ability is lacking. Here we report the production of hundreds of millions of iPfSPZ. iPfSPZ invaded human hepatocytes in culture and developed to mature liver-stage schizonts expressing P. falciparum merozoite surface protein 1 (PfMSP1) in numbers comparable to mPfSPZ. When injected into FRGhuHep mice containing humanized livers, iPfSPZ invaded the human hepatocytes and developed to PfMSP1-expressing late liver stage parasites at 45% the quantity of cryopreserved mPfSPZ. Human blood from FRGhuHep mice infected with iPfSPZ produced asexual and sexual erythrocytic-stage parasites in culture, and gametocytes developed to PfSPZ when fed to mosquitoes, completing the P. falciparum life cycle from infectious gametocyte to infectious gametocyte without mosquitoes or primates.

A combination of QTL mapping and genome-wide association study revealed the key gene for husk number in maize.

KEY MESSAGE: Two key genes Zm00001d021232 and Zm00001d048138 were identified by QTL mapping and GWAS. Additionally, they were verified to be significantly associated with maize husk number (HN) using gene-based association study. As a by-product of maize production, maize husk is an important industrial raw material. Husk layer number (HN) is an important trait that affects the yield of maize husk. However, the genetic mechanism underlying HN remains unclear. Herein, a total of 13 quantitative trait loci (QTL) controlling HN were identified in an IBM Syn 10 DH population across different locations. Among these, three QTL were individually repeatedly detected in at least two environments. Meanwhile, 26 unique single nucleotide polymorphisms (SNPs) were detected to be significantly (p < 2.15 × 10-6) associated with HN in an association pool. Of these SNPs, three were simultaneously detected across multiple environments or environments and best linear unbiased prediction (BLUP). We focused on these environment-stable and population-common genetic loci for excavating the candidate genes responsible for maize HN. Finally, 173 initial candidate genes were identified, of which 22 were involved in both multicellular organism development and single-multicellular organism process and thus confirmed as the candidate genes for HN. Gene-based association analyses revealed that the variants in four genes were significantly (p < 0.01/N) correlated with HN, of which Zm00001d021232 and Zm00001d048138 were highly expressed in husks and early developing ears among different maize tissues. Our study contributes to the understanding of genetic and molecular mechanisms of maize husk yield and industrial development in the future.

Sterile protection against human malaria by chemoattenuated PfSPZ vaccine.

A highly protective malaria vaccine would greatly facilitate the prevention and elimination of malaria and containment of drug-resistant parasites. A high level (more than 90%) of protection against malaria in humans has previously been achieved only by immunization with radiation-attenuated Plasmodium falciparum (Pf) sporozoites (PfSPZ) inoculated by mosquitoes; by intravenous injection of aseptic, purified, radiation-attenuated, cryopreserved PfSPZ ('PfSPZ Vaccine'); or by infectious PfSPZ inoculated by mosquitoes to volunteers taking chloroquine or mefloquine (chemoprophylaxis with sporozoites). We assessed immunization by direct venous inoculation of aseptic, purified, cryopreserved, non-irradiated PfSPZ ('PfSPZ Challenge') to malaria-naive, healthy adult volunteers taking chloroquine for antimalarial chemoprophylaxis (vaccine approach denoted as PfSPZ-CVac). Three doses of 5.12 × 104 PfSPZ of PfSPZ Challenge at 28-day intervals were well tolerated and safe, and prevented infection in 9 out of 9 (100%) volunteers who underwent controlled human malaria infection ten weeks after the last dose (group III). Protective efficacy was dependent on dose and regimen. Immunization with 3.2 × 103 (group I) or 1.28 × 104 (group II) PfSPZ protected 3 out of 9 (33%) or 6 out of 9 (67%) volunteers, respectively. Three doses of 5.12 × 104 PfSPZ at five-day intervals protected 5 out of 8 (63%) volunteers. The frequency of Pf-specific polyfunctional CD4 memory T cells was associated with protection. On a 7,455 peptide Pf proteome array, immune sera from at least 5 out of 9 group III vaccinees recognized each of 22 proteins. PfSPZ-CVac is a highly efficacious vaccine candidate; when we are able to optimize the immunization regimen (dose, interval between doses, and drug partner), this vaccine could be used for combination mass drug administration and a mass vaccination program approach to eliminate malaria from geographically defined areas.

Attenuated PfSPZ Vaccine induces strain-transcending T cells and durable protection against heterologous controlled human malaria infection.

A live-attenuated malaria vaccine, Plasmodium falciparum sporozoite vaccine (PfSPZ Vaccine), confers sterile protection against controlled human malaria infection (CHMI) with Plasmodium falciparum (Pf) parasites homologous to the vaccine strain up to 14 mo after final vaccination. No injectable malaria vaccine has demonstrated long-term protection against CHMI using Pf parasites heterologous to the vaccine strain. Here, we conducted an open-label trial with PfSPZ Vaccine at a dose of 9.0 × 105 PfSPZ administered i.v. three times at 8-wk intervals to 15 malaria-naive adults. After CHMI with homologous Pf parasites 19 wk after final immunization, nine (64%) of 14 (95% CI, 35-87%) vaccinated volunteers remained without parasitemia compared with none of six nonvaccinated controls (P = 0.012). Of the nine nonparasitemic subjects, six underwent repeat CHMI with heterologous Pf7G8 parasites 33 wk after final immunization. Five (83%) of six (95% CI, 36-99%) remained without parasitemia compared with none of six nonvaccinated controls. PfSPZ-specific T-cell and antibody responses were detected in all vaccine recipients. Cytokine production by T cells from vaccinated subjects after in vitro stimulation with homologous (NF54) or heterologous (7G8) PfSPZ were highly correlated. Interestingly, PfSPZ-specific T-cell responses in the blood peaked after the first immunization and were not enhanced by subsequent immunizations. Collectively, these data suggest durable protection against homologous and heterologous Pf parasites can be achieved with PfSPZ Vaccine. Ongoing studies will determine whether protective efficacy can be enhanced by additional alterations in the vaccine dose and number of immunizations.

Untethered microgripper-the dexterous hand at microscale.

Untethered microgrippers that can navigate in hard-to-reach and unpredictable environments are significantly important for biomedical applications such as targeted drug delivery, micromanipulation, minimally invasive surgery and in vivo biopsy. Compared with the traditional tethered microgrippers, the wireless microgrippers, due to the exceptional characteristics such as miniaturized size, untethered actuation, dexterous and autonomous motion, are projected to be promising microtools in various future applications. In this review, we categorize the untethered microgrippers into five major classes, i.e. microgrippers responsive to thermal, microgrippers actuated by magnetic fields, microgrippers responsive to chemicals, light-driven microgrippers and hybrid actuated microgrippers. Firstly, the actuation mechanisms of these microgrippers are introduced. The challenges faced by these microgrippers are also covered in this part. With that, the fabrication methods of these microgrippers are summarized. Subsequently, the applications of microgrippers are presented. Additionally, we conduct a comparison among different actuation mechanisms to explore the advantages and potential challenges of various types of microgrippers. In the end of this review, conclusions and outlook of the development and potential applications of the microgrippers are discussed.

Hysteresis and its impact on characterization of mechanical properties of suspended monolayer molybdenum-disulfide sheets.

The hysteresis phenomenon frequently arises in two-dimensional (2D) material nanoindentation, which is generally expected to be excluded from characterizing the elastic properties due to the imperfect elastic behaviour. However, the underlying mechanism of hysteresis and its effect on the characterization of the mechanical properties of 2D materials remain unclear. Cyclic loadings are exerted on the suspended monolayer molybdenum-disulfide (MoS2) films in atomic force microscopy (AFM) nanoindentation experiments. The elastic hysteresis loops are observed for most of the force-displacement curves. The friction/wear between the AFM silicon tip and the MoS2 monolayer is deemed to be dominant compared to the friction between the monolayer and the silicon dioxide substrate after the analysis, as determined using the finite element method (FEM) simulation. The loading force-displacement curves instead of the unloading curves have been used to deduce the elastic mechanical properties using a modified regression equation. The mean value of the obtained Young's modulus of monolayer MoS2, E, is equal to 209 ± 18 GPa, which is close to the inherent stiffness value, predicted by first principles calculation. Our results have confirmed that it is not obligatory to exclude the sample data with hysteresis behaviour for characterizing the elastic properties of 2D materials. In addition, all sample sheets have finally been penetrated and the mean breaking stress value, σmax, is 36.6 ± 0.9 GPa, determined using the radius value of the worn tip. Furthermore, the effect of the loading force and the shape/size of the suspended monolayer MoS2 sheets on the hysteresis behaviour in the 2D nanoindentation have also been analyzed and discussed, exhibiting interesting trends. Our findings provide guidance for the characterization of the mechanical properties of 2D materials using the AFM nanoindentation and the experimental samples with elastic hysteresis behaviour.

Development of a Live Attenuated Bivalent Oral Vaccine Against Shigella sonnei Shigellosis and Typhoid Fever.

Shigella sonnei and Salmonella Typhi cause significant morbidity and mortality. We exploited the safety record of the oral, attenuated S. Typhi vaccine (Ty21a) by using it as a vector to develop a bivalent oral vaccine to protect against S. sonnei shigellosis and typhoid fever. We recombineered the S. sonnei form I O-antigen gene cluster into the Ty21a chromosome to create Ty21a-Ss, which stably expresses S. sonnei form I O antigen. To enhance survivability in the acid environment of the stomach, we created an acid-resistant strain, Ty21a-AR-Ss, by inserting Shigella glutaminase-glutamate decarboxylase systems coexpressed with S. sonnei form I O-antigen gene. Mice immunized intranasally with Ty21a-AR-Ss produced antibodies against S. sonnei and S. Typhi, and survived lethal intranasal S. sonnei challenge. This paves the way for proposed good manufacturing practices manufacture and clinical trials intended to test the clinical effectiveness of Ty21a-AR-Ss in protecting against S. sonnei shigellosis and typhoid fever, as compared with the current Ty21a vaccine.

Abnormal nonlocal scale effect on static bending of single-layer MoS2.

The nonlocal scale parameter of nonlocal Euler-Bernoulli beam theory is evaluated for the static bending of single-layer molybdenum disulfide (SLMoS2) without predetermined bending rigidity. The evaluation is performed by matching the fitted curve between the maximum deflection and the beam length obtained from molecular mechanics simulations. It was observed that the fitted curves have an abnormal sign in the second-order term of the maximum deflection for SLMoS2, opposite to that for graphene and regardless of the interatomic interaction potentials used. Based on the nature of 'nonlocal' and the phenomenological point of view, a modified nonlocal constitutive relation with a positive sign in front of the higher-order term is suggested for SLMoS2. The nonlocal parameter and the bending rigidity of SLMoS2 are finally extracted, and the effect of the nonlocal scale parameter on the bending response for SLMoS2 is found to be significant for beam length less than a critical length, depending on both the interatomic interaction potentials and the boundary conditions. Our new perspective should be useful for researchers who are interested in the engineering application of graphene-like quasi-two-dimensional nanostructures using nonlocal beam theories.

Plasticity resulted from phase transformation for monolayer molybdenum disulfide film during nanoindentation simulations.

Molecular dynamics simulations on nanoindentation of circular monolayer molybdenum disulfide (MoS2) film are carried out to elucidate the deformation and failure mechanisms. Typical force-deflection curves are obtained, and in-plane stiffness of MoS2 is extracted according to a continuum mechanics model. The measured in-plane stiffness of monolayer MoS2 is about 182 ± 14 N m-1, corresponding to an effective Young's modulus of 280 ± 21 GPa. More interestingly, at a critical indentation depth, the loading force decreases sharply and then increases again. The loading-unloading-reloading processes at different initial unloading deflections are also conducted to explain the phenomenon. It is found that prior to the critical depth, the monolayer MoS2 film can return to the original state after completely unloading, while there is hysteresis when unloading after the critical depth and residual deformation exists after indenter fully retracted, indicating plasticity. This residual deformation is found to be caused by the changed lattice structure of the MoS2, i.e. a phase transformation. The critical pressure to induce the phase transformation is then calculated to be 36 ± 2 GPa, consistent with other studies. Finally, the influences of temperature, the diameter and indentation rate of MoS2 monolayer on the mechanical properties are also investigated.

Controllable Assembly and Separation of Colloidal Nanoparticles through a One-Tube Synthesis Based on Density Gradient Centrifugation.

Self-assembly of gold nanoparticles into one-dimensional (1D) nanostructures with finite primary units was achieved by introducing a thin salt (NaCl) solution layer into density gradient before centrifugation. The electrostatic interactions between Au nanoparticles would be affected and cause 1D assembly upon passing through the salt layer. A negatively charged polymer such as poly(acrylic acid) was used as an encapsulation/stabilization layer to help the formation of 1D Au assemblies, which were subsequently sorted according to unit numbers at succeeding separation zones. A centrifugal field was introduced as the external field to overcome the random Brownian motion of NPs and benefit the assembly effect. Such a facile "one-tube synthesis" approach couples assembly and separation in one centrifuge tube by centrifuging once. The method can be tuned by changing the concentration of interference salt layer, encapsulation layer, and centrifugation rate. Furthermore, positively charged fluorescent polymers such as perylenediimide-poly(N,N-diethylaminoethyl methacrylate) could encapsulate the assemblies to give tunable fluorescence properties.

Robust, reproducible, industrialized, standard membrane feeding assay for assessing the transmission blocking activity of vaccines and drugs against Plasmodium falciparum.

BACKGROUND: A vaccine that interrupts malaria transmission (VIMT) would be a valuable tool for malaria control and elimination. One VIMT approach is to identify sexual erythrocytic and mosquito stage antigens of the malaria parasite that induce immune responses targeted at disrupting parasite development in the mosquito. The standard Plasmodium falciparum membrane-feeding assay (SMFA) is used to assess transmission-blocking activity (TBA) of antibodies against candidate immunogens and of drugs targeting the mosquito stages. To develop its P. falciparum sporozoite (SPZ) products, Sanaria has industrialized the production of P. falciparum-infected Anopheles stephensi mosquitoes, incorporating quantitative analyses of oocyst and P. falciparum SPZ infections as part of the manufacturing process. METHODS: These capabilities were exploited to develop a robust, reliable, consistent SMFA that was used to assess 188 serum samples from animals immunized with the candidate vaccine immunogen, Pfs25, targeting P. falciparum mosquito stages. Seventy-four independent SMFAs were performed. Infection intensity (number of oocysts/mosquito) and infection prevalence (percentage of mosquitoes infected with oocysts) were compared between mosquitoes fed cultured gametocytes plus normal human O(+) serum (negative control), anti-Pfs25 polyclonal antisera (MRA39 or MRA38, at a final dilution in the blood meal of 1:54 as positive control), and test sera from animals immunized with Pfs25 (at a final dilution in the blood meal of 1:9). RESULTS: SMFA negative controls consistently yielded high infection intensity (mean = 46.1 oocysts/midgut, range of positives 3.7-135.6) and infection prevalence (mean = 94.2%, range 71.4-100.0) and in positive controls, infection intensity was reduced by 81.6% (anti-Pfs25 MRA39) and 97.0% (anti-Pfs25 MRA38), and infection prevalence was reduced by 12.9 and 63.5%, respectively. A range of TBAs was detected among the 188 test samples assayed in duplicate. Consistent administration of infectious gametocytes to mosquitoes within and between assays was achieved, and the TBA of anti-Pfs25 control antibodies was highly reproducible. CONCLUSIONS: These results demonstrate a robust capacity to perform the SMFA in a medium-to-high throughput format, suitable for assessing large numbers of experimental samples of candidate antibodies or drugs.

Improving sarcopenia in older adults: a systematic review and meta-analysis of randomized controlled trials of whey protein supplementation with or without resistance training.

OBJECTIVES: The aim of the study was to comprehensively analyze the effects of whey protein (WP)-enriched supplement intake with or without resistance training (RT) in older patients, either from the community or hospital, who were diagnosed with sarcopenia according to the EWGSOP or AWGS criteria. METHODS: This meta-analysis study was registered in PROSPERO (CRD42023407885). We searched the PubMed, Embase, Web of Science, and Cochrane Library databases for RCTs up to June 1, 2023. Standardized mean differences (SMD) with 95% confidence intervals (CI) were used to estimate the pooled results. RESULTS: Ten RCT studies, including 1154 participants, were included and analyzed. The primary outcomes were the changes in muscle mass, strength, and physical performance. In WP group versus (vs.) Isocaloric placebo (PLA)/Routine consultation (RC) group, WP significantly increased the appendicular skeletal muscle mass index (SMD: 0.47, 95%CI: 0.23, 0.71), appendicular skeletal muscle mass (SMD: 0.28, 95%CI: 0.11, 0.45) and gait speed (SMD: 1.13, 95%CI: 0.82, 1.44) in older patients with sarcopenia. In WP with RT group vs. PLA/ RC group, there was significant increase in handgrip strength (SMD: 0.67, 95%CI: 0.29, 1.04). In addition, in the secondary outcomes, WP significantly reduced interleukin-6, significantly increased insulin-like growth factor-1 and albumin, promoted participants' intake of total energy and protein, enhanced activities of daily living scores in patients, and had no significant effect on BMI, weight, or fat mass. CONCLUSION: This review confirms that WP can improve various aspects of older adult with sarcopenia, thereby enhancing their overall physical condition. More studies should be conducted to validate this result and further explore the effects of WP and RT in patients with sarcopenia.

Prognostic and clinicopathologic significance of PLIN2 in cancers: A systematic review with meta-analysis.

The relationship between PLIN2 expression and prognosis, and clinicopathological significance of various cancers has been extensively studied, but the results are not completely consistent. This review followed the guidelines for systematic reviews of prognostic factors studies and was reported under the Preferred Reporting Program for Systematic Reviews and Meta-Analysis (PRISMA). We searched PubMed, Embase, Cochrane Library, Web of Science, and Google Academia for relevant articles up to September 2, 2022, and calculated the pooled hazard ratios (HR) with 95% confidence intervals (CI) to determine the association between PLIN2 expression and the prognosis of various cancers. The meta-analysis ultimately included 17 studies. The quality of all included cohort studies was evaluated using the Quality in Prognosis Studies (QUIPS) tool, and an adaptation of Grading of Recommendations Assessment, Development and Evaluation (GRADE) method was used to assess the certainty of the results. High expression of PLIN2 was associated with poorer overall survival (HR = 1.65; 95% CI = 1.14, 2.38; P = 0.008), metastasis-free survival (HR = 1.48; 95% CI = 1.12, 1.94; P = 0.005), progression-free survival (HR = 2.11; 95% CI = 1.55, 2.87; P < 0.0005) and recurrence-free survival/relapse-free survival (HR = 2.21; 95% CI = 1.64, 2.98; P < 0.0005) in cancers. The clinicopathological parameters of digestive system malignancies suggested that high expression of PLIN2 was notably associated with distant metastasis ( + ) (odds ratio (OR) = 3.37; 95% CI = 1.31, 8.67; P = 0.012), lymph node metastasis ( + ) (OR = 1.61; 95% CI = 1.01, 2.54; P = 0.004), and tumor stage (III-IV) (OR = 1.96; 95% CI = 1.24, 3.09; P = 0.006). In summary, overexpression of PLIN2 is significantly associated with a poor prognosis in various human cancers, especially in respiratory and digestive malignancies. Thus, PLIN2 expression may be a potential prognostic biomarker in cancer patients.

Effect of Pre-Operative Low Serum Pre-Albumin on Surgical Site Infection in Post-Surgery Subjects: A Systematic Review and Meta-Analysis.

Background: The correlation between pre-operative serum pre-albumin and surgical site infection (SSI) has been the focus of many studies. However, existing literature presents conflicting evidence on this association. Therefore, this meta-analysis was conducted to determine the significance of low serum pre-albumin as a prognostic factor SSI, and to assess the potential utility of pre-albumin in predicting SSI. Methods: A comprehensive literature search and analysis was conducted in PubMed, Web of Science, Cochrane of Library, Scopus, Embase, and Google Scholar databases through August 2022 to identify studies reporting low pre-operative serum pre-albumin levels in patients undergoing surgery and their association with SSIs. The pooled risk estimates were shown in odds ratio with 95% confidence interval. The random effect model was used according to the test of heterogeneity among studies. Subgroup analyses and sensitivity analyses were performed to identify the possible sources of heterogeneity. This meta-analysis was prospectively registered in the PROSPERO database (number: CRD42022376167). Results: Nine studies involving 5,306 patients were eligible. The results demonstrated an association between low pre-operative serum pre-albumin levels and a higher probability of developing SSI (odds ratio [OR], 2.04; 95% confidence interval [CI], 1.28-3.26). Conclusions: Our findings suggest that low serum pre-albumin level may serve as an independent and valuable predictor of SSI. These results provide important insights for clinicians in identifying high-risk patients and implementing preventive measures.

Untargeted lipidomic analysis and network pharmacology for parthenolide treated papillary thyroid carcinoma cells.

BACKGROUND: With fast rising incidence, papillary thyroid carcinoma (PTC) is the most common head and neck cancer. Parthenolide, isolated from traditional Chinese medicine, inhibits various cancer cells, including PTC cells. The aim was to investigate the lipid profile and lipid changes of PTC cells when treated with parthenolide. METHODS: Comprehensive lipidomic analysis of parthenolide treated PTC cells was conducted using a UHPLC/Q-TOF-MS platform, and the changed lipid profile and specific altered lipid species were explored. Network pharmacology and molecular docking were performed to show the associations among parthenolide, changed lipid species, and potential target genes. RESULTS: With high stability and reproducibility, a total of 34 lipid classes and 1736 lipid species were identified. Lipid class analysis indicated that parthenolide treated PTC cells contained higher levels of fatty acid (FA), cholesterol ester (ChE), simple glc series 3 (CerG3) and lysophosphatidylglycerol (LPG), lower levels of zymosterol (ZyE) and Monogalactosyldiacylglycerol (MGDG) than controlled ones, but with no significant differences. Several specific lipid species were changed significantly in PTC cells treated by parthenolide, including the increasing of phosphatidylcholine (PC) (12:0e/16:0), PC (18:0/20:4), CerG3 (d18:1/24:1), lysophosphatidylethanolamine (LPE) (18:0), phosphatidylinositol (PI) (19:0/20:4), lysophosphatidylcholine (LPC) (28:0), ChE (22:6), and the decreasing of phosphatidylethanolamine (PE) (16:1/17:0), PC (34:1) and PC (16:0p/18:0). Four key targets (PLA2G4A, LCAT, LRAT, and PLA2G2A) were discovered when combining network pharmacology and lipidomics. Among them, PLA2G2A and PLA2G4A were able to bind with parthenolide confirmed by molecular docking. CONCLUSIONS: The changed lipid profile and several significantly altered lipid species of parthenolide treated PTC cells were observed. These altered lipid species, such as PC (34:1), and PC (16:0p/18:0), may be involved in the antitumor mechanisms of parthenolide. PLA2G2A and PLA2G4A may play key roles when parthenolide treated PTC cells.

A state-of-the-art review of functional magnetic resonance imaging technique integrated with advanced statistical modeling and machine learning for primary headache diagnosis.

Primary headache is a very common and burdensome functional headache worldwide, which can be classified as migraine, tension-type headache (TTH), trigeminal autonomic cephalalgia (TAC), and other primary headaches. Managing and treating these different categories require distinct approaches, and accurate diagnosis is crucial. Functional magnetic resonance imaging (fMRI) has become a research hotspot to explore primary headache. By examining the interrelationships between activated brain regions and improving temporal and spatial resolution, fMRI can distinguish between primary headaches and their subtypes. Currently the most commonly used is the cortical brain mapping technique, which is based on blood oxygen level-dependent functional magnetic resonance imaging (BOLD-fMRI). This review sheds light on the state-of-the-art advancements in data analysis based on fMRI technology for primary headaches along with their subtypes. It encompasses not only the conventional analysis methodologies employed to unravel pathophysiological mechanisms, but also deep-learning approaches that integrate these techniques with advanced statistical modeling and machine learning. The aim is to highlight cutting-edge fMRI technologies and provide new insights into the diagnosis of primary headaches.

Increased levels of anti-PfCSP antibodies in post-pubertal females versus males immunized with PfSPZ Vaccine does not translate into increased protective efficacy.

Background: While prior research has shown differences in the risk of malaria infection and sickness between males and females, little is known about sex differences in vaccine-induced immunity to malaria. Identifying such differences could elucidate important aspects of malaria biology and facilitate development of improved approaches to malaria vaccination. Methods: Using a standardized enzyme-linked immunosorbent assay, IgG antibodies to the major surface protein on Plasmodium falciparum (Pf) sporozoites (SPZ), the Pf circumsporozoite protein (PfCSP), were measured before and two weeks after administration of a PfSPZ-based malaria vaccine (PfSPZ Vaccine) to 5-month to 61-year-olds in 11 clinical trials in Germany, the US and five countries in Africa, to determine if there were differences in vaccine elicited antibody response between males and females and if these differences were associated with differential protection against naturally transmitted Pf malaria (Africa) or controlled human malaria infection (Germany, the US and Africa). Results: Females ≥ 11 years of age made significantly higher levels of antibodies to PfCSP than did males in most trials, while there was no indication of such differences in infants or children. Although adult females had higher levels of antibodies, there was no evidence of improved protection compared to males. In 2 of the 7 trials with sufficient data, protected males had significantly higher levels of antibodies than unprotected males, and in 3 other trials protected females had higher levels of antibodies than did unprotected females. Conclusion: Immunization with PfSPZ Vaccine induced higher levels of antibodies in post-pubertal females but showed equivalent protection in males and females. We conclude that the increased antibody levels in post-pubertal females did not contribute substantially to improved protection. We hypothesize that while antibodies to PfCSP (and PfSPZ) may potentially contribute directly to protection, they primarily correlate with other, potentially protective immune mechanisms, such as antibody dependent and antibody independent cellular responses in the liver.

Self-Assembled Peptide Nanofibers with Voltage-Regulated Inverse Photoconductance.

Inverse photoconductance is an uncommon phenomenon observed in selective low-dimensional materials, in which the electrical conductivity of the materials decreases under light illumination. The unique material property holds great promise for biomedical applications in photodetectors, photoelectric logic gates, and low-power nonvolatile memory, which remains a daunting challenge. Especially, tunable photoconductivity for biocompatible materials is highly desired for interfacing with biological systems but is less explored in organic materials. Here, we report nanofibers self-assembled with cyclo-tyrosine-tyrosine (cyclo-YY) having voltage-regulated inverse photoconductance and photoconductance. The peptide nanofibers can be switched back and forth by a bias voltage for imitating biological sensing in artificial vision and memory devices. A peptide optoelectronic resistive random access memory (PORRAM) device has also been fabricated using the nanofibers that can be electrically switched between long-term and short-term memory. The underlying mechanism of the reversible photoconductance is discussed in this paper. Due to the inherent biocompatibility of peptide materials, the reversible photoconductive nanofibers may have broad applications in sensing and storage for biotic and abiotic interfaces.

Development of a metabolically active, non-replicating sporozoite vaccine to prevent Plasmodium falciparum malaria.

Immunization of volunteers by the bite of mosquitoes carrying radiation-attenuated Plasmodium falciparum sporozoites protects greater than 90% of such volunteers against malaria, if adequate numbers of immunizing biting sessions and sporozoite-infected mosquitoes are used. Nonetheless, until recently it was considered impossible to develop, license and commercialize a live, whole parasite P. falciparum sporozoite (PfSPZ) vaccine. In 2003 Sanaria scientists reappraised the potential impact of a metabolically active, non-replicating PfSPZ vaccine, and outlined the challenges to producing such a vaccine. Six years later, significant progress has been made in overcoming these challenges. This progress has enabled the manufacture and release of multiple clinical lots of a 1(st) generation metabolically active, non-replicating PfSPZ vaccine, the Sanaria PfSPZ Vaccine, submission of a successful Investigational New Drug application to the US Food and Drug Administration, and initiation of safety, immunogenicity and protective efficacy studies in volunteers in MD, US. Efforts are now focused on how best to achieve submission of a successful Biologics License Application and introduce the vaccine to the primary target population of African children in the shortest possible period of time. This will require implementation of a systematic, efficient clinical development plan. Short term challenges include optimizing the (1) efficiency and scale up of the manufacturing process and quality control assays, (2) dosage regimen and method of administration, (3) potency of the vaccine, and (4) logistics of delivering the vaccine to those who need it most, and finalizing the methods for vaccine stabilization and attenuation. A medium term goal is to design and build a facility for manufacturing highly potent and stable vaccine for pivotal Phase 3 studies and commercial launch.

Atomic-Scale Friction on Monovacancy-Defective Graphene and Single-Layer Molybdenum-Disulfide by Numerical Analysis.

Using numerical simulations, we study the atomic-scale frictional behaviors of monovacancy-defective graphene and single-layer molybdenum-disulfide (SLMoS2) based on the classical Prandtl-Tomlinson (PT) model with a modified interaction potential considering the Schwoebel-Ehrlich barrier. Due to the presence of a monovacancy defect on the surface, the frictional forces were significantly enhanced. The effects of the PT model parameters on the frictional properties of monovacancy-defective graphene and SLMoS2 were analyzed, and it showed that the spring constant of the pulling spring cx is the most influential parameter on the stick-slip motion in the vicinity of the vacancy defect. Besides, monovacancy-defective SLMoS2 is found to be more sensitive to the stick-slip motion at the vacancy defect site than monovacancy-defective graphene, which can be attributed to the complicated three-layer-sandwiched atomic structure of SLMoS2. The result suggests that the soft tip with a small spring constant can be an ideal candidate for the observation of stick-slip behaviors of the monovacancy-defective surface. This study can fill the gap in atomic-scale friction experiments and molecular dynamics simulations of 2D materials with vacancy-related defects.