SARS-CoV-2 omicron spike simulations: broad antibody escape, weakened ACE2 binding, and modest furin cleavage.

The recent emergence of the omicron variant of the SARS-CoV-2 virus with large numbers of mutations has raised concern about a potential new surge in infections. Here we use molecular dynamics to study the biophysics of the interface of the BA1 and BA2 omicron spike protein binding to (i) the ACE2 receptor protein, (ii) antibodies from all known binding regions, and (iii) the furin binding domain. Our simulations suggest that while there is a significant reduction of antibody (Ab) binding strength corresponding to escape, the omicron spikes pay a cost in terms of weaker receptor binding as measured by interfacial hydrogen bonds (H-bond). The furin cleavage domain (FCD) is the same or weaker binding than the delta variant, suggesting lower fusogenicity resulting in less viral load and disease intensity than the delta variant. IMPORTANCE The BA1 and BA2 and closely related BA2.12.2 and BA.5 omicron variants of SARS-CoV-2 dominate the current global infection landscape. Given the high number of mutations, particularly those which will lead to antibody escape, it is important to establish accurate methods that can guide developing health policy responses that identify at a fundamental level whether omicron and its variants are more threatening than its predecessors, especially delta. The importance of our work is to demonstrate that simple in silico simulations can predict biochemical binding details of the omicron spike protein that have epidemiological consequences, especially for binding to the cells and for fusing the viral membrane with the cells. In each case, we predicted weaker binding of the omicron spike, which agreed with subsequent experimental results. Future virology experiments will be needed to test these predictions further.

Using machine learning to detect coronaviruses potentially infectious to humans.

Establishing the host range for novel viruses remains a challenge. Here, we address the challenge of identifying non-human animal coronaviruses that may infect humans by creating an artificial neural network model that learns from spike protein sequences of alpha and beta coronaviruses and their binding annotation to their host receptor. The proposed method produces a human-Binding Potential (h-BiP) score that distinguishes, with high accuracy, the binding potential among coronaviruses. Three viruses, previously unknown to bind human receptors, were identified: Bat coronavirus BtCoV/133/2005 and Pipistrellus abramus bat coronavirus HKU5-related (both MERS related viruses), and Rhinolophus affinis coronavirus isolate LYRa3 (a SARS related virus). We further analyze the binding properties of BtCoV/133/2005 and LYRa3 using molecular dynamics. To test whether this model can be used for surveillance of novel coronaviruses, we re-trained the model on a set that excludes SARS-CoV-2 and all viral sequences released after the SARS-CoV-2 was published. The results predict the binding of SARS-CoV-2 with a human receptor, indicating that machine learning methods are an excellent tool for the prediction of host expansion events.

Antibacterial Activity of a New Strain of Streptomyces maritimus MSQ21 against Ralstonia solanacearum.

<b>Background and Objective:</b> Actinobacteria represent the most prominent group of microorganisms, which produce a vast number of bioactive compounds especially antibiotics. The present study investigated the antibacterial activity of some actinomycete isolates against <i>Ralstonia solanacearum</i> type 3 biovar 2 (phytopathogenic bacterium that causes tomato wilt disease and brown rot of potatoes). <b>Materials and Methods:</b> The most potent actinomycete isolates in the antibacterial activity was further identified up to species based on its phenotypic and molecular characteristics. Additionally, the most suitable carbon and nitrogen sources for increasing the antibacterial activity were also investigated. <b>Results:</b> Interestingly, <i>Streptomyces </i>isolate MSQ21 achieved the highest antibacterial activity against <i>R. solanacearum</i> with an inhibition zone of 18 mm. 16S rRNA gene analysis suggested that <i>Streptomyces </i>MSQ21 was identified as a strain of <i>S. maritimus</i> Glycerol (2.25%, w/v) and (NH₄)₂SO₄ (0.13%, w/v) were the most suitable carbon and nitrogen sources for increasing the antibacterial activity. <b>Conclusion:</b> It could be concluded that the maximum antibacterial activity (30mm) produced by <i>S. maritimus </i>strain MSQ21 against <i>R. solanacearum </i>could be obtained by using the modified starch nitrate medium containing (g L¹): Glycerol, 25: Ammonium sulphate, 1.6: Dipotassium hydrogen phosphate, 1: Magnesium sulphate, 0.5: Sodium chloride, 0.5: Calcium carbonate, 3: Ferrous sulphate and 0.01: Distilled water up to 1 L and under the following conditions: Temperature 30°C, agitation speed 250 rpm, inoculum size 1-50 mL medium, incubation period 4 days and pH 8.5.

Seepage Characteristics of Mixed-Wettability Porous Media on the Phase-Field Model.

Clarifying the microscale gas-water flow behaviors in a mixed wettability reservoir is of great importance for underground engineering. A numerical model of mixed wettability based on circular particles was constructed using the MATLAB stochastic distribution program, and the gas-water flow was simulated based on the phase-field method. The Navier-Stokes equations were solved by the finite element method. The work analyzed the effects of the content of heterogeneous wetting particles, wettability, and inversed wettability of the matrix on the flow path and pressure distribution of the mixed wettability model. Besides, the two-phase flow behaviors were evaluated in microscale mixed-wettability porous media. The simulation results revealed that (i) the residual saturation of the gas phase showed a positive correlation with the hydrophobic particle content, and closed gases only existed in isolated pore channels with small content. Isolated closed gases gradually connected as the content increased. (ii) The residual gas content in the corner and tail end increased as the hydrophobicity of particles increased in hydrophilic matrices. Hydrophobic matrices showed a negative correlation, with the greatest pressure drop due to capillary resistance and step changes in the neutral-hydrophobic transition zone. (iii) Water-phase breakthrough time and gas-phase residual saturation showed a negative correlation change. The more space occupied by the gas phase, the faster the water-phase breakthrough. Moreover, the saturation no longer changes after the breakthrough. The work provides a guideline for determining the dominant flow path of phase displacements and the distribution of residual phases.

A primary squamous cell carcinoma of the sigmoid colon in a young patient: A case report and literature review.

Colon cancer is among the most common types of cancer with adenocarcinomas being the most common type. Herein we report a young patient who presented with primary colonic squamous cell carcinoma without risk factors. To the best of our knowledge, this is the youngest patient with such diagnosis worldwide.

Amplifying Lateral Flow Assay Signals for Rapid Detection of COVID-19 Specific Antibodies.

Rapid lateral flow immune-assays are point-of-care diagnostic tools that are easy to use, cheap, and do not need centralized infrastructure. Therefore, these devices are appealing for rapid detection of the humoral immune responses to infections, particularly severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The novel technique introduced here uses a complex of anti-SARS-CoV-2 N-protein antibodies conjugated to gold nanoparticles that are bound to five SARS-CoV-2 N protein conjugated to gold nanoparticles to amplify the signals obtained from the conjugated SARS-CoV-2 N protein and to enhance the assay detection limit. To validate the performance of the adopted lateral flow, serum from SARS-CoV-2 seropositive individuals and prepandamic negative samples are tested and compared to a validated enzyme-linked immunosorbent assay (ELISA) for the detection of SARS-CoV-2 N protein specific IgG and IgM antibodies. The data shows that the designed lateral flow assay has an excellent sensitivity and specificity upon detecting IgM and IgG antibodies by applying only 2 µL from the serum sample to the adopted strips. Taken together, the developed lateral flow immunoassay assay provides a rapid, specific, and highly sensitive means to detect the immune responses against SARS-CoV-2 with only 2 µL from the serum sample.

Granulomatous and xanthogranulomatous prostatitis: A case report.

Granulomatous prostatitis is a rare condition that is diagnosed only by histopathological examination. Though rare, the condition was reported to have different presentations (mimicking prostate cancer or prostatitis and prostatic abscess) and to have different etiologies which classified it into three main entities; nonspecific (idiopathic), post-surgery, and specific. Specific granulomatous prostatitis is further sub-classified to infective, xanthogranulomatous, Malacoplakia and associated with systemic granulomatous disease and allergy. We hereby report a rare case of xanthogranulomatous prostatitis that presented with persistent urinary tract infection.

Synthetic SARS-CoV-2 Spike-Based DNA Vaccine Elicits Robust and Long-Lasting Th1 Humoral and Cellular Immunity in Mice.

The ongoing global pandemic of coronavirus disease 2019 (COVID-19) calls for an urgent development of effective and safe prophylactic and therapeutic measures. The spike (S) glycoprotein of severe acute respiratory syndrome-coronavirus (SARS-CoV-2) is a major immunogenic and protective protein and plays a crucial role in viral pathogenesis. In this study, we successfully constructed a synthetic codon-optimized DNA-based vaccine as a countermeasure against SARS-CoV-2, denoted VIU-1005. The design was based on a codon-optimized coding sequence of a consensus full-length S glycoprotein. The immunogenicity of the vaccine was tested in two mouse models (BALB/c and C57BL/6J). Th1-skewed systemic S-specific IgG antibodies and neutralizing antibodies (nAbs) were significantly induced in both models 4 weeks after three injections with 100 µg of the VIU-1005 vaccine via intramuscular needle injection but not intradermal or subcutaneous routes. Such immunization induced long-lasting IgG and memory T cell responses in mice that lasted for at least 6 months. Interestingly, using a needle-free system, we showed an enhanced immunogenicity of VIU-1005 in which lower or fewer doses were able to elicit significantly high levels of Th1-biased systemic S-specific immune responses, as demonstrated by the significant levels of binding IgG antibodies, nAbs and IFN-γ, TNF and IL-2 cytokine production from memory CD8+ and CD4+ T cells in BALB/c mice. Furthermore, compared to intradermal needle injection, which failed to induce any significant immune response, intradermal needle-free immunization elicited a robust Th1-biased humoral response similar to that observed with intramuscular immunization. Together, our results demonstrate that the synthetic VIU-1005 candidate DNA vaccine is highly immunogenic and capable of inducing long-lasting Th1-skewed humoral and cellular immunity in mice. Furthermore, we show that the use of a needle-free system could enhance the immunogenicity and minimize doses needed to induce protective immunity in mice, supporting further preclinical and clinical testing of this candidate vaccine.

Enhanced immunogenicity of a synthetic DNA vaccine expressing consensus SARS-CoV-2 Spike protein using needle-free immunization

The ongoing global pandemic of Coronavirus Disease 2019 (COVID-19) calls for an urgent development of effective and safe prophylactic and therapeutic measures. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) glycoprotein is a major immunogenic and protective protein, and plays a crucial role in viral pathogenesis. In this study, we successfully constructed a synthetic codon-optimized DNA-based vaccine as a countermeasure against SARS-CoV-2; denoted as VIU-1005. The design was based on the synthesis of codon-optimized coding sequence for optimal mammalian expression of a consensus full-length S glycoprotein. The successful construction of the vaccine was confirmed by restriction digestion and sequencing, and the protein expression of the S protein was confirmed by western blot and immunofluorescence staining in mammalian cells. The immunogenicity of the vaccine was tested in two mouse models (BALB/c and C57BL/6J). Th1-skewed systemic S-specific IgG antibodies and neutralizing antibodies (nAbs) were significantly induced in both models four weeks post three injections with 100 g of the VIU-1005 vaccine via intramuscular needle injection but not intradermal or subcutaneous routes. Importantly, such immunization induced long-lasting IgG response in mice that lasted for at least 6 months. Interestingly, using a needle-free system, we showed an enhanced immunogenicity of VIU-1005 in which lower doses such as 25-50 g or less number of doses were able to elicit significantly high levels of Th1-biased systemic S-specific IgG antibodies and nAbs via intramuscular immunization compared to needle immunization. Compared to the intradermal needle injection which failed to induce any significant immune response, intradermal needle-free immunization elicited robust Th1-biased humoral response similar to that observed with intramuscular immunization. Furthermore, immunization with VIU-1005 induced potent S-specific cellular response as demonstrated by the significantly high levels of IFN-{gamma}, TNF and IL-2 cytokines production in memory CD8+ and CD4+ T cells in BALB/c mice. Together, our results demonstrate that the synthetic VIU-1005 candidate DNA vaccine is highly immunogenic and capable of inducing long-lasting and Th1-skewed immune response in mice. Furthermore, we show that the use of needle-free system could enhance the immunogenicity and minimize doses needed to induce protective immunity in mice, supporting further preclinical and clinical testing of this candidate vaccine.

Early Humoral Response Correlates with Disease Severity and Outcomes in COVID-19 Patients.

The Coronavirus Disease 2019 (COVID-19), caused by SARS-CoV-2, continues to spread globally with significantly high morbidity and mortality rates. Antigen-specific responses are of unquestionable value for clinical management of COVID-19 patients. Here, we investigated the kinetics of IgM, IgG against the spike (S) and nucleoproteins (N) proteins and their neutralizing capabilities in hospitalized COVID-19 patients with different disease presentations (i.e., mild, moderate or severe), need for intensive care units (ICU) admission or outcomes (i.e., survival vs death). We show that SARS-CoV-2 specific IgG, IgM and neutralizing antibodies (nAbs) were readily detectable in almost all COVID-19 patients with various clinical presentations. Interestingly, significantly higher levels of nAbs as well as anti-S1 and -N IgG and IgM antibodies were found in patients with more severe symptoms, patients requiring admission to ICU or those with fatal outcomes. More importantly, early after symptoms onset, we found that the levels of anti-N antibodies correlated strongly with disease severity. Collectively, these findings provide new insights into the kinetics of antibody responses in COVID-19 patients with different disease severity.

Overlapping variants in the blood, tissues and cell lines for patients with intracranial meningiomas are predominant in stem cell-related genes.

OBJECTIVE: Bulk tissue genomic analysis of meningiomas identified common somatic mutations, however, it often excluded blood-related variants. In contrast, genomic characterisation of primary cell lines that can provide critical information regarding growth and proliferation, have been rare. In our work, we identified the variants that are present in the blood, tissues and corresponding cell lines that are likely to be predictive, tumorigenic and progressive. METHOD: Whole-exome sequencing was used to identify variants and distinguish related pathways that exist in 42 blood, tissues and corresponding cell lines (BTCs) samples for patients with intracranial meningiomas. Conventional sequencing was used for the confirmation of variants. Integrative analysis of the gene expression for the corresponding samples was utilised for further interpretations. RESULTS: In total, 926 BTC variants were detected, implicating 845 genes. A pathway analysis of all BTC genes with damaging variants indicated the 'cell morphogenesis involved in differentiation' stem cell-related pathway to be the most frequently affected pathway. Concordantly, five stem cell-related genes, GPRIN2, ALDH3B2, ASPN, THSD7A and SIGLEC6, showed BTC variants in at least five of the patients. Variants that were heterozygous in the blood and homozygous in the tissues or the corresponding cell lines were rare (average: 1.3 ± 0.3%), and included variants in the RUNX2 and CCDC114 genes. An analysis comparing the variants detected only in tumours with aggressive features indicated a total of 240 BTC genes, implicating the 'homophilic cell adhesion via plasma membrane adhesion molecules' pathway, and identifying the stem cell-related transcription coactivator NCOA3/AIB1/SRC3 as the most frequent BTC gene. Further analysis of the possible impact of the poly-Q mutation present in the NCOA3 gene indicated associated deregulation of 15 genes, including the up-regulation of the stem cell related SEMA3D gene and the angiogenesis related VEGFA gene. CONCLUSION: Stem cell-related pathways and genes showed high prevalence in the BTC variants, and novel variants in stem cell-related genes were identified for meningioma. These variants can potentially be used as predictive, tumorigenic and progressive biomarkers for meningioma.

Performance of Commercially Available Rapid Serological Assays for the Detection of SARS-CoV-2 Antibodies.

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to spread globally. Although several rapid commercial serological assays have been developed, little is known about their performance and accuracy in detecting SARS-CoV-2-specific antibodies in COVID-19 patient samples. Here, we have evaluated the performance of seven commercially available rapid lateral flow immunoassays (LFIA) obtained from different manufacturers, and compared them to in-house developed and validated ELISA assays for the detection of SARS-CoV-2-specific IgM and IgG antibodies in RT-PCR-confirmed COVID-19 patients. While all evaluated LFIA assays showed high specificity, our data showed a significant variation in sensitivity of these assays, which ranged from 0% to 54% for samples collected early during infection (3-7 days post symptoms onset) and from 54% to 88% for samples collected at later time points during infection (8-27 days post symptoms onset). Therefore, we recommend prior evaluation and validation of these assays before being routinely used to detect IgM and IgG in COVID-19 patients. Moreover, our findings suggest the use of LFIA assays in combination with other standard methods, and not as an alternative.

Evaluation of Neutralizing Antibodies Against Highly Pathogenic Coronaviruses: A Detailed Protocol for a Rapid Evaluation of Neutralizing Antibodies Using Vesicular Stomatitis Virus Pseudovirus-Based Assay.

Emerging highly pathogenic human coronaviruses (CoVs) represent a serious ongoing threat to the public health worldwide. The spike (S) proteins of CoVs are surface glycoproteins that facilitate viral entry into host cells via attachment to their respective cellular receptors. The S protein is believed to be a major immunogenic component of CoVs and a target for neutralizing antibodies (nAbs) and most candidate vaccines. Development of a safe and convenient assay is thus urgently needed to determine the prevalence of CoVs nAbs in the population, to study immune response in infected individuals, and to aid in vaccines and viral entry inhibitor evaluation. While live virus-based neutralization assays are used as gold standard serological methods to detect and measure nAbs, handling of highly pathogenic live CoVs requires strict bio-containment conditions in biosafety level-3 (BSL-3) laboratories. On the other hand, use of replication-incompetent pseudoviruses bearing CoVs S proteins could represent a safe and useful method to detect nAbs in serum samples under biosafety level-2 (BSL-2) conditions. Here, we describe a detailed protocol of a safe and convenient assay to generate vesicular stomatitis virus (VSV)-based pseudoviruses to evaluate and measure nAbs against highly pathogenic CoVs. The protocol covers methods to produce VSV pseudovirus bearing the S protein of the Middle East respiratory syndrome-CoV (MERS-CoV) and the severe acute respiratory syndrome-CoV-2 (SARS-CoV-2), pseudovirus titration, and pseudovirus neutralization assay. Such assay could be adapted by different laboratories and researchers working on highly pathogenic CoVs without the need to handle live viruses in the BSL-3 environment.

Early Humoral Response Correlates with Disease Severity and Outcomes in COVID-19 Patients

The Coronavirus Disease 2019 (COVID-19), caused by the novel SARS-CoV-2, continues to spread globally with significantly high morbidity and mortality rates. Immunological surrogate markers, in particular antigen-specific responses, are of unquestionable value for clinical management of patients with COVID-19. Here, we investigated the kinetics of IgM, IgG against the spike (S) and nucleoproteins (N) proteins and their neutralizing capabilities in hospitalized patients with RT-PCR confirmed COVID-19 infection. Our data show that SARS-CoV-2 specific IgG, IgM and neutralizing antibodies (nAbs) were readily detectable in almost all COVID-19 patients with various clinical presentations. Notably, anti-S and -N IgG, peaked 20-40 day after disease onset, and were still detectable for at least up to 70 days, with nAbs observed during the same time period. Moreover, nAbs titers were strongly correlated with IgG antibodies. Significantly higher levels of nAbs as well as anti-S1 and N IgG and IgM antibodies were found in patients with more severe clinical presentations, patients requiring admission to intensive care units (ICU) or those with fatal outcomes. Interestingly, lower levels of antibodies, particularly anti-N IgG and IgM in the first 15 days after symptoms onset, were found in survivors and those with mild clinical presentations. Collectively, these findings provide new insights into the characteristics and kinetics of antibody responses in COVID-19 patients with different disease severity.

Neuroectodermal stem cells: A remyelinating potential in acute compressed spinal cord injury in rat model.

The outcomes of compressed spinal cord injury (CSCI) necessitate radical treatment. The therapeutic potential of neuroectodermal stem cells (NESCs) in a rat model of CSCI in acute and subacute stages was assessed. White Wistar rat were divided into control, sham-operated, CSCI untreated model, CSCI grafted with NESCs at 1 day after CSCI, and at 7 days after CSCI. Primary NESC cultures were prepared from brains of embryonic day 10 (E10) mice embryos. NESCs were transplanted at the site of injury using a Hamilton syringe. Locomotor functional assessment, routine histopathology, immunostaining for (GFAP), and ultrastructure techniques for evaluating the CSI were conducted. In CSCI, areas of hemorrhage, cavitation, reactive astrocytosis, upregulated GFAP expression of immunostained areas, degeneration of the axoplasm and demyelination were observed. One day after grafting with NESCs, a decrease in astrocyte reaction and pathological features, quantitative and qualitative enhancement of remyelination and improved locomotor activity were observed. Treatment with NESCs at 7 days after CSCI did not mitigatethe reactive astrocytosis and glial scar formation that hindered the ability of the NESCs to enhance remyelination of axons. In conclusion, the microenvironment and time of NESCs transplantation affect activity of astrocytes and remyelination of axons.

Effect of Very Low Dose Fast Neutrons on the DNA of Rats' Peripheral Blood Mononuclear Cells and Leukocytes.

The effect of very low dose fast neutrons on the chromatin and DNA of rats' peripheral blood mononuclear cells (PBMC) and leukocytes has been studied in the present work using Fourier transform infrared (FTIR) and single-cell gel electrophoresis (comet assay). Fourteen female Wistar rats were used; seven were irradiated with neutrons of 0.9 cGy (Am-Be, 0.02 cGy h(-1)), and seven others were used as control. Second derivative and curve fitting were used to analyze the FTIR spectra. In addition, hierarchical cluster analysis (HCA) was used to classify the group spectra. Meanwhile, the tail moment and percentage of DNA in the tail were used as indicators to sense the breaking and the level of damage in DNA. The analysis of FTIR spectra of the PBMC of the irradiated group revealed a marked increase in the area of phosphodiesters of nucleic acids and the area ratios of RNA/DNA and phosphodiesters/carbohydrates. A sharp significant increase and decrease in the areas of RNA and DNA ribose were recorded, respectively. In the irradiated group, leukocytes with different tail lengths were observed. The distributions of tail moments and the percentage of DNA in the tail of irradiated groups were heterogeneous. The mean value of the percentages of DNA in the tail at 0.5 h post-irradiation represented low-level damage in the DNA. Therefore, one can conclude that very low dose fast neutrons might cause changes in the DNA of PBMC at the submolecular level. It could cause low-level damage, double-strand break, and chromatin fragmentation of DNA of leukocytes.

Genotoxicity of waterpipe smoke in buccal cells and peripheral blood leukocytes as determined by comet assay.

CONTEXT: Waterpipe smoke causes DNA damage in peripheral blood leukocytes and in buccal cells of smokers. OBJECTIVE: To determine the exposure effect of waterpipe smoke on buccal cells and peripheral blood leukocytes in regard to DNA damage using comet assay. MATERIALS AND METHODS: The waterpipe smoke condensates were analyzed by gas chromatography-mass spectrometry (GC-MS). The study was performed on 20 waterpipe smokers. To perform comet assay on bucaal cells of smokers, 10 µl of cell suspension was mixed with 85 µl of pre-warmed 1% low melting agarose, applied to comet slide and electrophoresed. To analyze the effect of smoke condensate in vitro, 1 ml of peripheral blood was mixed with 10 µl of smoke condensate and subjected for comet assay. RESULTS: The GC-MS analysis revealed the presence of 2,3-dihydro-3,5-dihydroxy-6-methyl-4H-pyran-4on, nicotine, hydroxymethyl furancarboxaldehyde and 3-ethoxy-4-hydroxybenzaldehyde in the smoke condensates. Waterpipe smoking caused DNA damage in vivo in buccal cells of smokers. The tail moment and tail length in buccal cells of smokers were 186 ± 26 and 456 ± 71, respectively, which are higher than control. The jurak and moassel smoke condensates were found to cause DNA damage in peripheral blood leukocytes. The moassel smoke condensate was more damaging. DISCUSSION: There is wide misconception that waterpipe smoking is not as harmful as cigarette smoking. This study demonstrated that waterpipe smoke induced DNA damage in exposed cells. CONCLUSION: Waterpipe smokes cause DNA damage in buccal cells. The smoke condensate of both jurak and moassel caused comet formation suggesting DNA damage in peripheral blood leukocytes.

Hippocampal and cortical primary cilia are required for aversive memory in mice.

It has been known for decades that neurons throughout the brain possess solitary, immotile, microtubule based appendages called primary cilia. Only recently have studies tried to address the functions of these cilia and our current understanding remains poor. To determine if neuronal cilia have a role in behavior we specifically disrupted ciliogenesis in the cortex and hippocampus of mice through conditional deletion of the Intraflagellar Transport 88 (Ift88) gene. The effects on learning and memory were analyzed using both Morris Water Maze and fear conditioning paradigms. In comparison to wild type controls, cilia mutants displayed deficits in aversive learning and memory and novel object recognition. Furthermore, hippocampal neurons from mutants displayed an altered paired-pulse response, suggesting that loss of IFT88 can alter synaptic properties. A variety of other behavioral tests showed no significant differences between conditional cilia mutants and controls. This type of conditional allele approach could be used to distinguish which behavioral features of ciliopathies arise due to defects in neural development and which result from altered cell physiology. Ultimately, this could lead to an improved understanding of the basis for the cognitive deficits associated with human cilia disorders such as Bardet-Biedl syndrome, and possibly more common ailments including depression and schizophrenia.

Community-based cardiovascular Risk Factors Intervention Strategies (CORFIS) in managing hypertension: A pragmatic non-randomised controlled trial.

BACKGROUND: Hypertension is the number one cardiovascular risk factor in Malaysia. This study aimed to evaluate the effectiveness of a Community-Based Cardiovascular Risk Factors Intervention Strategies (CORFIS) in the management of hypertension in primary care. METHODS: This is a pragmatic, non-randomized controlled trial. Seventy general practitioners (GPs) were selected to provide either CORFIS (44 GPs) or conventional care (26 GPs) for 6 months. A total of 486 hypertensive patients were recruited; 309 were in the intervention and 177 in the control groups. Primary outcome was the proportion of hypertensive patients who achieved target blood pressure (BP) of <140/90mmHg (for those without diabetes mellitus) and <130/80mmHg (with diabetes mellitus). Secondary outcomes include change in the mean/median BP at 6-month as compared to baseline. RESULTS: The proportion of hypertensive patients who achieved target BP at 6-month was significantly higher in the CORFIS arm (69.6%) as compared to the control arm (57.6%), P=0.008. Amongst those who had uncontrolled BP at baseline, the proportion who achieved target BP at 6-month was also significantly higher in the CORFIS arm (56.6%) as compared to the control arm (34.1%), p<0.001. There was no difference in the patients who had already achieved BP control at baseline. There were significant reductions in SBP in the CORFIS arm (median -9.0mmHg; -60 to 50) versus control (median -2mmHg; -50 to 48), p=0.003; as well as in DBP (CORFIS arm: median -6.0mmHg; ranged from -53 to 30 versus control arm: median 0.0mmHg; ranged from -42 to 30), p<0.001. CONCLUSIONS: Patients who received CORFIS care demonstrated significant improvements in achieving target BP.