Disease-Causing Mutations in SF3B1 Alter Splicing by Disrupting Interaction with SUGP1.

SF3B1, which encodes an essential spliceosomal protein, is frequently mutated in myelodysplastic syndromes (MDS) and many cancers. However, the defect of mutant SF3B1 is unknown. Here, we analyzed RNA sequencing data from MDS patients and confirmed that SF3B1 mutants use aberrant 3' splice sites. To elucidate the underlying mechanism, we purified complexes containing either wild-type or the hotspot K700E mutant SF3B1 and found that levels of a poorly studied spliceosomal protein, SUGP1, were reduced in mutant spliceosomes. Strikingly, SUGP1 knockdown completely recapitulated the splicing errors, whereas SUGP1 overexpression drove the protein, which our data suggest plays an important role in branchsite recognition, into the mutant spliceosome and partially rescued splicing. Other hotspot SF3B1 mutants showed similar altered splicing and diminished interaction with SUGP1. Our study demonstrates that SUGP1 loss is a common defect of spliceosomes with disease-causing SF3B1 mutations and, because this defect can be rescued, suggests possibilities for therapeutic intervention.

SF3B1 mutant-induced missplicing of MAP3K7 causes anemia in myelodysplastic syndromes.

SF3B1 is the most frequently mutated RNA splicing factor in cancer, including in ∼25% of myelodysplastic syndromes (MDS) patients. SF3B1-mutated MDS, which is strongly associated with ringed sideroblast morphology, is characterized by ineffective erythropoiesis, leading to severe, often fatal anemia. However, functional evidence linking SF3B1 mutations to the anemia described in MDS patients harboring this genetic aberration is weak, and the underlying mechanism is completely unknown. Using isogenic SF3B1 WT and mutant cell lines, normal human CD34 cells, and MDS patient cells, we define a previously unrecognized role of the kinase MAP3K7, encoded by a known mutant SF3B1-targeted transcript, in controlling proper terminal erythroid differentiation, and show how MAP3K7 missplicing leads to the anemia characteristic of SF3B1-mutated MDS, although not to ringed sideroblast formation. We found that p38 MAPK is deactivated in SF3B1 mutant isogenic and patient cells and that MAP3K7 is an upstream positive effector of p38 MAPK. We demonstrate that disruption of this MAP3K7-p38 MAPK pathway leads to premature down-regulation of GATA1, a master regulator of erythroid differentiation, and that this is sufficient to trigger accelerated differentiation, erythroid hyperplasia, and ultimately apoptosis. Our findings thus define the mechanism leading to the severe anemia found in MDS patients harboring SF3B1 mutations.

BDNF/TrkB activators in Parkinson's disease: A new therapeutic strategy.

Parkinson's disease (PD) is a neurodegenerative disorder of the brain and is manifested by motor and non-motor symptoms because of degenerative changes in dopaminergic neurons of the substantia nigra. PD neuropathology is associated with mitochondrial dysfunction, oxidative damage and apoptosis. Thus, the modulation of mitochondrial dysfunction, oxidative damage and apoptosis by growth factors could be a novel boulevard in the management of PD. Brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin receptor kinase type B (TrkB) are chiefly involved in PD neuropathology. BDNF promotes the survival of dopaminergic neurons in the substantia nigra and enhances the functional activity of striatal neurons. Deficiency of the TrkB receptor triggers degeneration of dopaminergic neurons and accumulation of α-Syn in the substantia nigra. As well, BDNF/TrkB signalling is reduced in the early phase of PD neuropathology. Targeting of BDNF/TrkB signalling by specific activators may attenuate PD neuropathology. Thus, this review aimed to discuss the potential role of BDNF/TrkB activators against PD. In conclusion, BDNF/TrkB signalling is decreased in PD and linked with disease severity and long-term complications. Activation of BDNF/TrkB by specific activators may attenuate PD neuropathology.

Molecular insights into expression and silencing of resistance determinants in Staphylococcus aureus.

OBJECTIVE: This study aimed to investigate the status of antimicrobial-resistant strains of Staphylococcus aureus in Pakistan, their association in terms of co-occurrence with the biofilm-forming genes, resistance profiling and associated discrepancies in diagnostic methods. METHODOLOGY: A total of 384 milk samples from bovine was collected by using convenient sampling technique and were initially screened for subclinical mastitis, further preceded by isolation and confirmation of S. aureus. The S. aureus isolates were subjected to evaluation of antimicrobial resistance by phenotypic identification using Kirby-Bauer disc diffusion method, while the genotypic estimation was done by polymerase chain reaction to declare isolates as methicillin, beta-lactam, vancomycin, tetracycline, and aminoglycoside resistant S. aureus (MRSA, BRSA, VRSA, TRSA, and ARSA), respectively. RESULTS: The current study revealed an overall prevalence of subclinical mastitis and S. aureus to be 59.11% and 46.69%, respectively. On a phenotypic basis, the prevalence of MRSA, BRSA, VRSA, TRSA, and ARSA was found to be 44.33%, 58.49%, 20.75%, 35.84%, and 30.18%, respectively. The results of PCR analysis showed that 46.80% of the tested isolates were declared as MRSA, 37.09% as BRSA, and 36.36% as VRSA, while the occurrence of TRSA and ARSA was observed in 26.31% and 18.75%, respectively. The current study also reported the existence of biofilm-producing genes (icaA and icaD) in 49.06% and 40.57% isolates, respectively. Lastly, this study also reported a high incidence of discrepancies for both genotypic and phenotypic identification methods of resistance evaluation, with the highest discrepancy ratio for the accA-aphD gene, followed by tetK, vanB, blaZ, and mecA genes. CONCLUSION: The study concluded that different antibiotic resistance strains of S. aureus are prevalent in study districts with high potential to transmit between human populations. The study also determined that there are multiple resistance determinants and mechanisms that are responsible for the silencing and expression of antibiotic resistance genes.

Taurine/chenodeoxycholic acid ratio as a potential serum biomarker for low vitamin B12 levels in humans.

Deficiency of vitamin B12 (B12 or cobalamin), an essential water-soluble vitamin, leads to neurological damage, which can be irreversible and anaemia, and is sometimes associated with chronic disorders such as osteoporosis and cardiovascular diseases. Clinical tests to detect B12 deficiency lack specificity and sensitivity. Delays in detecting B12 deficiency pose a major threat because the progressive decline in organ functions may go unnoticed until the damage is advanced or irreversible. Here, using targeted unbiased metabolomic profiling in the sera of subjects with low B12 levels v control individuals, we set out to identify biomarker(s) of B12 insufficiency. Metabolomic profiling identified seventy-seven metabolites, and partial least squares discriminant analysis and hierarchical clustering analysis showed a differential abundance of taurine, xanthine, hypoxanthine, chenodeoxycholic acid, neopterin and glycocholic acid in subjects with low B12 levels. Random forest multivariate analysis identified a taurine/chenodeoxycholic acid ratio, with an AUC score of 1, to be the best biomarker to predict low B12 levels. Mechanistic studies using a mouse model of B12 deficiency showed that B12 deficiency reshaped the transcriptomic and metabolomic landscape of the cell, identifying a downregulation of methionine, taurine, urea cycle and nucleotide metabolism and an upregulation of Krebs cycle. Thus, we propose taurine/chenodeoxycholic acid ratio in serum as a potential biomarker of low B12 levels in humans and elucidate using a mouse model of cellular metabolic pathways regulated by B12 deficiency.

U2AF35(S34F) Promotes Transformation by Directing Aberrant ATG7 Pre-mRNA 3' End Formation.

Recurrent mutations in the splicing factor U2AF35 are found in several cancers and myelodysplastic syndrome (MDS). How oncogenic U2AF35 mutants promote transformation remains to be determined. Here we derive cell lines transformed by the oncogenic U2AF35(S34F) mutant and identify aberrantly processed pre-mRNAs by deep sequencing. We find that in U2AF35(S34F)-transformed cells the autophagy-related factor 7 (Atg7) pre-mRNA is abnormally processed, which unexpectedly is not due to altered splicing but rather selection of a distal cleavage and polyadenylation (CP) site. This longer Atg7 mRNA is translated inefficiently, leading to decreased ATG7 levels and an autophagy defect that predisposes cells to secondary mutations, resulting in transformation. MDS and acute myeloid leukemia patient samples harboring U2AF35(S34F) have a similar increased use of the ATG7 distal CP site, and previous studies have shown that mice with hematopoietic cells lacking Atg7 develop an MDS-like syndrome. Collectively, our results reveal a basis for U2AF35(S34F) oncogenic activity.

Dual role of mesenchymal stem/stromal cells and their cell-free extracellular vesicles in colorectal cancer.

Colorectal cancer (CRC) is one of the main causes of cancer-related deaths. However, the surgical control of the CRC progression is difficult, and in most cases, the metastasis leads to cancer-related mortality. Mesenchymal stem/stromal cells (MSCs) with potential translational applications in regenerative medicine have been widely researched for several years. MSCs could affect tumor development through secreting exosomes. The beneficial properties of stem cells are attributed to their cell-cell interactions as well as the secretion of paracrine factors in the tissue microenvironment. For several years, exosomes have been used as a cell-free therapy to regulate the fate of tumor cells in a tumor microenvironment. This review discusses the recent advances and current understanding of assessing MSC-derived exosomes for possible cell-free therapy in CRC.

Systematic Review of Arthroscopic Bankart Repair Outcomes for Anterior Shoulder Instability.

BACKGROUND The shoulder is a complex joint that has the most extensive range of motion among all joints, resulting in more susceptibility to dislocation. The treatment for acute shoulder dislocation is closed reduction, which should be performed immediately. Arthroscopic Bankart repair (ABR) is a procedure for treating anterior shoulder instability. This systematic review aimed to evaluate the published literature on ABR for anterior shoulder instability. MATERIAL AND METHODS We searched electronic databases, including Google Scholar, PubMed, Science Direct, Scopus, and PubMed, to find literature about our topic published between 2018 and 2023. Different keywords were searched, including "ABR, shoulder, instability, dislocation, treatment, management, recurrence, outcomes, and complications". The inclusion criteria were English original articles with available full text. RESULTS Only 8 articles were included; the articles included a total of 398 patients with an age range of 15 to 55 years old. One study was conducted on male patients, and another was conducted on female patients, whereas the remaining studies were conducted on both sexes. Among the 8 studies, 4 studies conducted ABR alone, and all reported significant change with ABR. Four studies compared ABR with Latarjet, concomitant remplissage, and immobilization and reported that ABR is equivalent or better than these interventions. CONCLUSIONS ABR was effective in the management of shoulder instability, as it resulted in a lower rate of recurrence, low rate of complications, and high rate of return to sport, regardless of the suture type. However, it is superior or similar to other interventions, like Latarjet and concomitant remplissage.

Nanoparticle Augmentation of Adhesive Systems: Impact on Tensile Strength in Fiberglass Post Placement within Root Dentin.

BACKGROUND Modification of the glass fiber post (GFP) with titanium dioxide or silver particles can improve the durability and reliability of dental treatments for ensuring long-term success. This research assessed the tensile bond strength (TBS) of an adhesive system used for cementing GFPs into root dentin following the incorporation of nanoparticles of titanium dioxide (NTiO2) and silver (NAg). MATERIAL AND METHODS Sixty human maxillary canines were prepared to create a 10-mm intra-radicular space for post placement from the cementoenamel junction. The specimens were randomly allocated into 2 groups (a non-thermocycling group and a thermocycling group). Each group was divided into 3 subgroups (10 samples each) according to the adhesive system used (adhesive system devoid of any addition, adhesive system including 1% NAg, and adhesive system infused with 1% NTiO2). TBS tests were conducted and recorded in MPa using a Universal Testing Machine, with an axial load applied at a rate of 0.5 mm/min until failure. The TBS for both groups (non-thermocycling and thermocycling) was measured in megapascals (MPa), and the failure type was recorded. The data were statistically analyzed using one-way analysis of variance (ANOVA) and Tukey's test with P.

The prevalence of probable overactive bladder and associated risk factors among medical students in Jordan: a cross-sectional study.

BACKGROUND: To discuss the impact of overactive bladder (OAB) on medical students. overactive bladder. is a chronic condition that causes sudden and intense urges to urinate, which can have significant physical and psychological effects on patients' lives. The prevalence of OAB among medical students is relatively high, with some studies reporting rates as high as 35.4%. This research aims to shed light on the prevalence rates and risk factors associated with OAB among medical students in Jordan. METHODS: A cross-sectional study was conducted using an online self-reported questionnaire as the study tool. The questionnaire collected the sociodemographic, health, and academic characteristics of medical students, as well as the new 7-item OABSS score. RESULTS: Out of the total sample of medical students surveyed (n = 525), 44.5% reported experiencing symptoms of OAB. Furthermore, the analysis also revealed that there was a significant difference in the prevalence of OAB between the ages of medical students. In addition, the study also found that there was a significant association between OAB symptoms and basic years, positive history of diagnostic UTI, positive history of recent trauma, high stress, and taking certain medications. CONCLUSIONS: The study highlights the need for further research in this area and emphasizes the possible implications of OAB for medical students, including the need for additional support and resources to manage the condition.

The prevalence of sedentary behavior among university students in Saudi Arabia.

BACKGROUND: A considerable body of research has demonstrated that reducing sitting time benefits health. Therefore, the current study aimed to explore the prevalence of sedentary behavior (SB) and its patterns. METHODS: A total of 6975 university students (49.1% female) were chosen randomly to participate in a face-to-face interview. The original English version of the sedentary behavior questionnaire (SBQ) was previously translated into Arabic. Then, the validated Arabic version of the SBQ was used to assess SB. The Arabic SBQ included 9 types of SB (watching television, playing computer/video games, sitting while listening to music, sitting and talking on the phone, doing paperwork or office work, sitting and reading, playing a musical instrument, doing arts and crafts, and sitting and driving/riding in a car, bus or train) on weekdays and weekends. RESULTS: SBQ indicated that the total time of SB was considerably high (478.75 ± 256.60 and 535.86 ± 316.53 (min/day) during weekdays and weekends, respectively). On average, participants spent the most time during the day doing office/paperwork (item number 4) during weekdays (112.47 ± 111.11 min/day) and weekends (122.05 ± 113.49 min/day), followed by sitting time in transportation (item number 9) during weekdays (78.95 ± 83.25 min/day) and weekends (92.84 ± 100.19 min/day). The average total sitting time of the SBQ was 495.09 ± 247.38 (min/day) and 58.4% of the participants reported a high amount of sitting time (≥ 7 hours/day). Independent t-test showed significant differences (P ≤ 0.05) between males and females in all types of SB except with doing office/paperwork (item number 4). The results also showed that male students have a longer daily sitting time (521.73 ± 236.53 min/day) than females (467.38 ± 255.28 min/day). Finally, 64.1% of the males reported a high amount of sitting time (≥ 7 hours/day) compared to females (52.3%). CONCLUSION: In conclusion, the total mean length of SB in minutes per day for male and female university students was considerably high. About 58% of the population appeared to spend ≥7 h/day sedentary. Male university students are likelier to sit longer than female students. Our findings also indicated that SB and physical activity interventions are needed to raise awareness of the importance of adopting an active lifestyle and reducing sitting time.

Investigating colostomy-related morbidity in children following stoma formation and closure in a tertiary hospital, Abha, Saudi Arabia: a retrospective cohort study 2024.

BACKGROUND: Overall, stoma-related morbidity affects a reported 20-38% of pediatric patients. However, determining the true incidence of major stoma-related morbidity is challenging due to limited cohort sizes in existing studies. Thus, the aim of this study was to investigate colostomy related morbidity among children both after stoma formation and stoma closure. METHODOLOGY: This is a retrospective cohort hospital-based study, conducted in an Abha maternity and children hospital, between August 1, 2018, and August 1, 2023, among 126 pediatric patients (aged 0-12 years) who underwent colostomy formation and subsequent closure during the study period. Data were collected from medical records. Data was analyzed using Statistical Package for Social Sciences (SPSS) v.26. RESULTS: This study included a total of 126 children who underwent colostomy. (N = 37, 29.4%) of cases included in this study were emergency cases, while (N = 89, 70.6%) were elective. A variety of antibiotics were used for surgical prophylaxis, metronidazole (77%) and cefuroxime (62.7%) were the most prevalent. Oral feeding was started after 5-6 days in more than one third of cases (39.7%). Wound infection (N = 15, 11.9%) was the most reported post-operative complication, followed with bowel obstruction (N = 6, 4.8%). Emergency cases had a longer duration of hospital stay than elective cases; this difference was statistically significant (P = .04). CONCLUSIONS: Majority of patients reported no stoma related complications, while among those who reported complications, wound infection was the most reported complication, followed by bowel obstruction.

The Prevalence and Awareness of Congenital External Ear Deformity among the School-Age Group: A Cross-Sectional Study.

INTRODUCTION AND PURPOSE: Congenital outer ear deformities stem from a sequence of disturbances during fetal auricular cartilage embryonic development. A significant gap exists in understanding their prevalence among the school-age group in Saudi Arabia. This cross-sectional study aims to address this knowledge gap to raise awareness about the impact of such disorders. METHODOLOGY: This cross-sectional study targeted parents of children in the school-age group. A multistage cluster sampling technique was employed to ensure the representation of schools. A self-administered Google form survey was used. Data were analyzed using IBM SPSS Statistics for Windows, Version 28.0 (IBM Corp., Armonk, NY). RESULTS: Our study revealed that the majority were males (56.2%), aged 6 to 10 years (49.3%), and attended primary school (69.5%). Chronic illnesses were present in 7.1% of children, with hearing impairment most prevalent (25.9%). Congenital ear deformities affected 2.7% of children, primarily Stahl's ear (35.4%). Limited knowledge about these deformities was observed among respondents (30.3%), yet a significant majority (73.9%) expressed belief in the potential of community awareness to decrease deformity prevalence. The awareness levels were impacted by parental education but showed no significant association with the child's age, gender, or presence of chronic diseases. CONCLUSION: Our study underscores the noteworthy occurrence of congenital ear deformities among the school-age group, coupled with a notable lack of awareness. Parental education emerges as a key factor influencing awareness levels. It is imperative to prioritize initiatives to bolster awareness and early detection to promote child health.

ASXL1 mutations are associated with a response to alvocidib and 5-azacytidine combination in myelodysplastic neoplasms.

Inhibitors of anti-apoptotic BCL-2 family proteins in combination with chemotherapy and hypomethylating agents (HMAs) are promising therapeutic approaches in acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS). Alvocidib, a cyclin-dependent kinase 9 (CDK9) inhibitor and indirect transcriptional repressor of the anti-apoptotic factor MCL-1, has previously shown clinical activity in AML. Availability of biomarkers for response to the alvocidib + 5- AZA could also extend the rationale of this treatment concept to high-risk MDS. In this study, we performed a comprehensive in vitro assessment of alvocidib and 5-AZA effects in n=45 high-risk MDS patients. Our data revealed additive cytotoxic effects of the combination treatment. Mutational profiling of MDS samples identified ASXL1 mutations as predictors of response. Further, increased response rates were associated with higher gene-expression of the pro-apoptotic factor NOXA in ASXL1 mutated samples. The higher sensitivity of ASXL1 mutant cells to the combination treatment was confirmed in vivo in ASXL1Y588X transgenic mice. Overall, our study demonstrated augmented activity for the alvocidib + 5-AZA combination in higher-risk MDS and identified ASXL1 mutations as a biomarker of response for potential stratification studies.

Cost and quality of operational larviciding using drones and smartphone technology.

BACKGROUND: Larval Source Management (LSM) is an important tool for malaria vector control and is recommended by WHO as a supplementary vector control measure. LSM has contributed in many successful attempts to eliminate the disease across the Globe. However, this approach is typically labour-intensive, largely due to the difficulties in locating and mapping potential malarial mosquito breeding sites. Previous studies have demonstrated the potential for drone imaging technology to map malaria vector breeding sites. However, key questions remain unanswered related to the use and cost of this technology within operational vector control. METHODS: Using Zanzibar (United Republic of Tanzania) as a demonstration site, a protocol was collaboratively designed that employs drones and smartphones for supporting operational LSM, termed the Spatial Intelligence System (SIS). SIS was evaluated over a four-month LSM programme by comparing key mapping accuracy indicators and relative costs (both mapping costs and intervention costs) against conventional ground-based methods. Additionally, malaria case incidence was compared between the SIS and conventional study areas, including an estimation of the incremental cost-effectiveness of switching from conventional to SIS larviciding. RESULTS: The results demonstrate that the SIS approach is significantly more accurate than a conventional approach for mapping potential breeding sites: mean % correct per site: SIS = 60% (95% CI 32-88%, p = 0.02), conventional = 18% (95% CI - 3-39%). Whilst SIS cost more in the start-up phase, overall annualized costs were similar to the conventional approach, with a simulated cost per person protected per year of $3.69 ($0.32 to $15.12) for conventional and $3.94 ($0.342 to $16.27) for SIS larviciding. The main economic benefits were reduced labour costs associated with SIS in the pre-intervention baseline mapping of habitats. There was no difference in malaria case incidence between the three arms. Cost effectiveness analysis showed that SIS is likely to provide similar health benefits at similar costs compared to the conventional arm. CONCLUSIONS: The use of drones and smartphones provides an improved means of mapping breeding sites for use in operational LSM. Furthermore, deploying this technology does not appear to be more costly than a conventional ground-based approach and, as such, may represent an important tool for Malaria Control Programmes that plan to implement LSM.

Elevated total and direct bilirubin are associated with acute complicated appendicitis: a single-center based study in Saudi Arabia.

BACKGROUND: Appendicitis is the most common abdominal surgical emergency and up to our knowledge no previous studies have been conducted in Saudi Arabia particularly at Qassim region and this study aimed to determine a total and direct bilirubin as a predictor of acute complicated appendicitis. METHODS: Observational retrospective study that included patients admitted under the general surgery department with a diagnosis of acute appendicitis at King Saud Hospital, Unaizah, Saudi Arabia. Data on age, gender, BMI, diabetes mellitus, total and direct bilirubin, AST, ALT, sodium, and WBCs levels were obtained. RESULT: Among the overall study population of 158 patients, the age median [IQR] was 24.5 [19-31], males were 99 (62.7%), and complicated appendicitis was 33 (20.9%). The multivariable analysis revealed that both elevated total and direct bilirubin are associated with complicated appendicitis (aOR = 3.79, 95% CI: 1.67-8.48, P = 0.001) and (aOR = 4.74, 95% CI: 2.07-10.86, P < 0.001) respectively. A receiver operating characteristic curve showed the best cutoff value of total and direct bilirubin as ≥ 15 µmol/L and ≥ 5 µmol/L respectively, with a sensitivity of 57.6%, and specificity of 73.6% for elevated total bilirubin, and a sensitivity of 54.6%, and specificity of 80% for elevated direct bilirubin. CONCLUSION: Elevated total and direct bilirubin are associated with acute complicated appendicitis in this setting. However, it should be supportive factor for acute complicated appendicitis and not considered as standalone diagnostic test.

A Novel Image Classification Method Based on Residual Network, Inception, and Proposed Activation Function.

In deeper layers, ResNet heavily depends on skip connections and Relu. Although skip connections have demonstrated their usefulness in networks, a major issue arises when the dimensions between layers are not consistent. In such cases, it is necessary to use techniques such as zero-padding or projection to match the dimensions between layers. These adjustments increase the complexity of the network architecture, resulting in an increase in parameter number and a rise in computational costs. Another problem is the vanishing gradient caused by utilizing Relu. In our model, after making appropriate adjustments to the inception blocks, we replace the deeper layers of ResNet with modified inception blocks and Relu with our non-monotonic activation function (NMAF). To reduce parameter number, we use symmetric factorization and 1×1 convolutions. Utilizing these two techniques contributed to reducing the parameter number by around 6 M parameters, which has helped reduce the run time by 30 s/epoch. Unlike Relu, NMAF addresses the deactivation problem of the non-positive number by activating the negative values and outputting small negative numbers instead of zero in Relu, which helped in enhancing the convergence speed and increasing the accuracy by 5%, 15%, and 5% for the non-noisy datasets, and 5%, 6%, 21% for non-noisy datasets.

Outdoor biting and pyrethroid resistance as potential drivers of persistent malaria transmission in Zanzibar.

BACKGROUND: Low-level of malaria transmission persist in Zanzibar despite high coverage of core vector control interventions. This study was carried out in hot-spot sites to better understand entomological factors that may contribute to residual malaria transmission in Zanzibar. METHODS: A total of 135 households were randomly selected from six sites and consented to participate with 20-25 households per site. Mosquito vector surveillance was carried out indoors and outdoors from 6:00 pm-7:00 am using miniaturized double net trap (DN-Mini™). Additional collections were done indoors using mouth aspirators to retrieve resting mosquitoes from wall and ceiling surfaces, and outdoors using resting bucket and pit traps. All collected mosquitoes were morphologically and genetically (PCR) analysed in the laboratory. All collected anopheline and blood-fed mosquitoes were analysed for sporozoite infection and blood meal host preferences by Circumsporozoite Protein ELISA and blood meal ELISA, respectively. The differences between indoor and outdoor mosquito biting rates were analysed using generalized linear mixed models. Levels of resistance to commonly used insecticides were quantified by WHO susceptibility tests. RESULTS: Out of 704 malaria vectors collected across 135 households, PCR analysis shows that 98.60% were Anopheles arabiensis, 0.6% Anopheles merus and 0.6% Anopheles gambiae sensu stricto. Sporozoite ELISA analysis indicates that all mosquitoes were negative for the malaria parasite. The results show that more An. arabiensis were collected outdoor (~ 85%) compared to indoor (~ 15%). Furthermore, large numbers of An. arabiensis were caught in outdoor resting sites, where the pit trap (67.2%) collected more mosquitoes compared to the outdoor DN-Mini trap (32.8%). Nearly two-thirds (60.7%) of blood-fed mosquitoes had obtained blood meals from non-human hosts. Mosquitoes displayed non-uniform susceptibility status and resistance intensity among the tested insecticides across the study sites to all WHO recommended insecticides across the study sites. CONCLUSION: This study suggests that in contexts such as Zanzibar, testing of novel techniques to complement indoor protection and targeting outdoor biting and/or resting mosquitoes, may be warranted to complement existing interventions and contribute to malaria elimination efforts. The study highlights the need to implement novel interventions and/or adaptations of strategies that can target outdoors biting mosquitoes.

Gene-edited stem cells enable CD33-directed immune therapy for myeloid malignancies.

Antigen-directed immunotherapies for acute myeloid leukemia (AML), such as chimeric antigen receptor T cells (CAR-Ts) or antibody-drug conjugates (ADCs), are associated with severe toxicities due to the lack of unique targetable antigens that can distinguish leukemic cells from normal myeloid cells or myeloid progenitors. Here, we present an approach to treat AML by targeting the lineage-specific myeloid antigen CD33. Our approach combines CD33-targeted CAR-T cells, or the ADC Gemtuzumab Ozogamicin with the transplantation of hematopoietic stem cells that have been engineered to ablate CD33 expression using genomic engineering methods. We show highly efficient genetic ablation of CD33 antigen using CRISPR/Cas9 technology in human stem/progenitor cells (HSPC) and provide evidence that the deletion of CD33 in HSPC doesn't impair their ability to engraft and to repopulate a functional multilineage hematopoietic system in vivo. Whole-genome sequencing and RNA sequencing analysis revealed no detectable off-target mutagenesis and no loss of functional p53 pathways. Using a human AML cell line (HL-60), we modeled a postremission marrow with minimal residual disease and showed that the transplantation of CD33-ablated HSPCs with CD33-targeted immunotherapy leads to leukemia clearance, without myelosuppression, as demonstrated by the engraftment and recovery of multilineage descendants of CD33-ablated HSPCs. Our study thus contributes to the advancement of targeted immunotherapy and could be replicated in other malignancies.

Deep Ensemble Fake News Detection Model Using Sequential Deep Learning Technique.

Recently, fake news has been widely spread through the Internet due to the increased use of social media for communication. Fake news has become a significant concern due to its harmful impact on individual attitudes and the community's behavior. Researchers and social media service providers have commonly utilized artificial intelligence techniques in the recent few years to rein in fake news propagation. However, fake news detection is challenging due to the use of political language and the high linguistic similarities between real and fake news. In addition, most news sentences are short, therefore finding valuable representative features that machine learning classifiers can use to distinguish between fake and authentic news is difficult because both false and legitimate news have comparable language traits. Existing fake news solutions suffer from low detection performance due to improper representation and model design. This study aims at improving the detection accuracy by proposing a deep ensemble fake news detection model using the sequential deep learning technique. The proposed model was constructed in three phases. In the first phase, features were extracted from news contents, preprocessed using natural language processing techniques, enriched using n-gram, and represented using the term frequency-inverse term frequency technique. In the second phase, an ensemble model based on deep learning was constructed as follows. Multiple binary classifiers were trained using sequential deep learning networks to extract the representative hidden features that could accurately classify news types. In the third phase, a multi-class classifier was constructed based on multilayer perceptron (MLP) and trained using the features extracted from the aggregated outputs of the deep learning-based binary classifiers for final classification. The two popular and well-known datasets (LIAR and ISOT) were used with different classifiers to benchmark the proposed model. Compared with the state-of-the-art models, which use deep contextualized representation with convolutional neural network (CNN), the proposed model shows significant improvements (2.41%) in the overall performance in terms of the F1score for the LIAR dataset, which is more challenging than other datasets. Meanwhile, the proposed model achieves 100% accuracy with ISOT. The study demonstrates that traditional features extracted from news content with proper model design outperform the existing models that were constructed based on text embedding techniques.