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1.
Nat Commun ; 15(1): 4187, 2024 May 17.
Article in English | MEDLINE | ID: mdl-38760381

ABSTRACT

Hypervirulent Klebsiella pneumoniae (hvKp) is a significant cause of severe invasive infections in Vietnam, yet data on its epidemiology, population structure and dynamics are scarce. We screened hvKp isolates from patients with bloodstream infections (BSIs) at a tertiary infectious diseases hospital in Vietnam and healthy individuals, followed by whole genome sequencing and plasmid analysis. Among 700 BSI-causing Kp strains, 100 (14.3%) were hvKp. Thirteen hvKp isolates were identified from 350 rectal swabs of healthy adults; none from 500 rectal swabs of healthy children. The hvKp isolates were genetically diverse, encompassing 17 sequence types (STs), predominantly ST23, ST86 and ST65. Among the 113 hvKp isolates, 14 (12.6%) carried at least one antimicrobial resistance (AMR) gene, largely mediated by IncFII, IncR, and IncA/C plasmids. Notably, the acquisition of AMR conjugative plasmids facilitated horizontal transfer of the non-conjugative virulence plasmid between K. pneumoniae strains. Phylogenetic analysis demonstrated hvKp isolates from BSIs and human carriage clustered together, suggesting a significant role of intestinal carriage in hvKp transmission. Enhanced surveillance is crucial to understand the factors driving intestinal carriage and hvKp transmission dynamics for informing preventive measures. Furthermore, we advocate the clinical use of our molecular assay for diagnosing hvKp infections to guide effective management.


Subject(s)
Klebsiella Infections , Klebsiella pneumoniae , Phylogeny , Plasmids , Whole Genome Sequencing , Klebsiella pneumoniae/genetics , Klebsiella pneumoniae/pathogenicity , Klebsiella pneumoniae/isolation & purification , Vietnam/epidemiology , Humans , Plasmids/genetics , Klebsiella Infections/epidemiology , Klebsiella Infections/microbiology , Virulence/genetics , Adult , Female , Gene Transfer, Horizontal , Male , Genome, Bacterial , Middle Aged , Anti-Bacterial Agents/pharmacology , Child , Genomics , Drug Resistance, Bacterial/genetics
3.
Public Health Nutr ; : 1-37, 2024 May 28.
Article in English | MEDLINE | ID: mdl-38804077

ABSTRACT

OBJECTIVE: SEANUTS II Vietnam aims to obtain an in-depth understanding of the nutritional status and nutrient intake of children between 0.5-11.9 years old. DESIGN: Cross-sectional survey. SETTING: A multistage cluster systematic random sampling method was implemented in different regions in Vietnam: North Mountainous, Central Highlands, Red River Delta, North Central and Coastal Area, Southeast and Mekong River Delta. PARTICIPANTS: 4001 children between 6 months and 11.9 years of age. RESULTS: Prevalence of stunting and underweight was higher in rural than in urban children, whereas overweight and obese rates were higher in urban areas. 12.0% of the children had anemia and especially children 0.5-1-year-old were affected (38.6%). Low serum retinol was found in 6.2% of children ≥ 4 years old. Prevalence of vitamin D insufficiency was 31.1% while 60.8% had low serum zinc. For nutrient intake, overall, 80.1% of the children did not meet the estimated energy requirements. For calcium intake, ∼60% of the younger children did not meet the RNI while it was 92.6% in children >7 years old. For vitamin D intake, 95.0% of the children did not meet RNI. CONCLUSIONS: SEANUTS II Vietnam indicated that overnutrition was more prevalent than undernutrition in urban areas, while undernutrition was found more in rural areas. The high prevalence of low serum zinc, vitamin D insufficiency and the inadequate intakes of calcium and vitamin D are of concern. Nutrition strategies for Vietnamese children should consider three sides of malnutrition and focus on approaches for the prevention malnutrition.

4.
Res Sq ; 2024 May 17.
Article in English | MEDLINE | ID: mdl-38798660

ABSTRACT

Alzheimer's disease (AD) is a progressive form of dementia affecting almost 55 million people worldwide. It is characterized by the abnormal deposition of amyloid plaques and neurofibrillary tangles within the brain, leading to a pathological cascade of neuron degeneration and death as well as memory loss and cognitive decline. Amyloid beta (Aß) is an AD biomarker present in cerebrospinal fluid and blood serum and correlates with the presence of amyloid plaques and tau tangles in the brain. Measuring the levels of Aß can help with early diagnosis of AD, which is key for studying novel AD drugs and delaying the symptoms of dementia. However, this goal is difficult to achieve due to the low levels of AD biomarkers in biofluids. Here we demonstrate for the first time the use of FLOWER (frequency locked optical whispering evanescent resonator) for quantifying the levels of post-mortem cerebrospinal fluid (CSF) Aß42 in clinicopathologically classified control, mild cognitive impairment (MCI), and AD participants. FLOWER is capable of measuring CSF Aß42 (area under curve, AUC = 0.92) with higher diagnostic performance than standard ELISA (AUC = 0.82) and was also able to distinguish between control and MCI samples. Our results demonstrate the capability of FLOWER for screening CSF samples for early diagnosis of Alzheimer's pathology.

5.
Environ Microbiol ; 26(6): e16657, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38817079

ABSTRACT

The health of bees can be assessed through their microbiome, which serves as a biomarker indicating the presence of both beneficial and harmful microorganisms within a bee community. This study presents the characterisation of the bacterial, fungal, and plant composition on the cuticle of adult bicoloured sweat bees (Agapostemon virescens). These bees were collected using various methods such as pan traps, blue vane traps and sweep netting across the northern extent of their habitat range. Non-destructive methods were employed to extract DNA from the whole pinned specimens of these wild bees. Metabarcoding of the 16S rRNA, ITS and rbcL regions was then performed. The study found that the method of collection influenced the detection of certain microbial and plant taxa. Among the collection methods, sweep net samples showed the lowest fungal alpha diversity. However, minor differences in bacterial or fungal beta diversity suggest that no single method is significantly superior to others. Therefore, a combination of techniques can cater to a broader spectrum of microbial detection. The study also revealed regional variations in bacterial, fungal and plant diversity. The core microbiome of A. virescens comprises two bacteria, three fungi and a plant association, all of which are commonly detected in other wild bees. These core microbes remained consistent across different collection methods and locations. Further extensive studies of wild bee microbiomes across various species and landscapes will help uncover crucial relationships between pollinator health and their environment.


Subject(s)
Bacteria , Biodiversity , Fungi , Microbiota , RNA, Ribosomal, 16S , Animals , Bees/microbiology , Fungi/classification , Fungi/genetics , Fungi/isolation & purification , Bacteria/classification , Bacteria/genetics , Bacteria/isolation & purification , RNA, Ribosomal, 16S/genetics , Flowers/microbiology , Plants/microbiology
6.
Curr Dev Nutr ; 8(6): 102063, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38817706

ABSTRACT

Background: Adolescent nutrition has faced a policy neglect, partly owing to the gaps in dietary intake data for this age group. The Food Recognition Assistance and Nudging Insights (FRANI) is a smartphone application validated for dietary assessment and to influence users toward healthy food choices. Objectives: This study aimed to assess the feasibility (adherence, acceptability, and usability) of FRANI and its effects on food choices and diet quality in female adolescents in Vietnam. Methods: Adolescents (N = 36) were randomly selected from a public school and allocated into 2 groups. The control group received smartphones with a version of FRANI limited to dietary assessment, whereas the intervention received smartphones with gamified FRANI. After the first 4 wk, both groups used gamified FRANI for further 2 wk. The primary outcome was the feasibility of using FRANI as measured by adherence (the proportion of completed food records), acceptability and usability (the proportion of participants who considered FRANI acceptable and usable according to answers of a Likert questionnaire). Secondary outcomes included the percentage of meals recorded, the Minimum Dietary Diversity for Women (MDDW) and the Eat-Lancet Diet Score (ELDS). Dietary diversity is important for dietary quality, and sustainable healthy diets are important to reduce carbon emissions. Poisson regression models were used to estimate the effect of gamified FRANI on the MDDW and ELDS. Results: Adherence to the application was 82% and the percentage of meals recorded was 97%. Acceptability and usability were 97%. MDDW in the intervention group was 1.07 points (95% CI: 0.98, 1.18; P = 0.13) greater than that in the control (constant = 4.68); however, the difference was not statistically significant. Moreover, ELDS in the intervention was 1.09 (95% CI: 1.01, 1.18; P = 0.03) points greater than in the control (constant = 3.67). Conclusions: FRANI was feasible and may be effective to influence users toward healthy food choices. Research is needed for FRANI in different contexts and at scale.The trial was registered at the International Standard Randomized Controlled Trial Number as ISRCTN 10681553.

7.
Heliyon ; 10(10): e31503, 2024 May 30.
Article in English | MEDLINE | ID: mdl-38818209

ABSTRACT

Recently, agriculture systems have faced numerous challenges involving sustainable nutrient use efficiency and feeding, environmental pollution especially heavy metals (HMs), infection of harmful microorganisms, and maintenance of crop production quality during postharvesting and packaging. Nanotechnology and nanomaterials have emerged as powerful tools in agriculture applications that provide alternatives or support traditional methods. This review aims to address and highlight the current overarching issue and various implementation strategies of nanotechnology for sustainable agriculture development. In particular, the current progress of different nano-fertilizers (NFs) systems was analyzed to show their advances in enhancing the uptake and translocations in plants and improving nutrient bioavailability in soil. Also, the design strategy and application of nanotechnology for rapid detection of HMs and pathogenic diseases in plant crops were emphasized. The engineered nanomaterials have great potential for biosensors with high sensitivity and selectivity, high signal throughput, and reproducibility through various detection approaches such as Raman, colorimetric, biological, chemical, and electrical sensors. We obtain that the development of microfluidic and lab-on-a-chip (LoC) technologies offers the opportunity to create on-site portable and smart biodevices and chips for real-time monitoring of plant diseases. The last part of this work is a brief introduction to trends in nanotechnology for harvesting and packaging to provide insights into the overall applications of nanotechnology for crop production quality. This review provides the current advent of nanotechnology in agriculture, which is essential for further studies examining novel applications for sustainable agriculture.

9.
J Biol Chem ; : 107418, 2024 May 28.
Article in English | MEDLINE | ID: mdl-38815867

ABSTRACT

ATP-citrate lyase (ACLY) links carbohydrate and lipid metabolism and provides nucleocytosolic acetyl-CoA necessary for protein acetylation. ACLY has two major splice isoforms: the full-length canonical "long" isoform and an uncharacterized "short" isoform in which exon 14 is spliced out. Exon 14 encodes 10 amino acids within a disordered region of the protein and includes at least 1 site that is dynamically phosphorylated. Both isoforms are expressed in healthy tissues to varying degrees. Analysis of human transcriptomic data revealed that the Percent Spliced In (PSI) of exon 14, i.e., the proportion of long isoform, is increased in several cancers and correlated with poorer overall survival in a pan-cancer analysis, though not in individual tumor types, which prompted us to explore potential biochemical and functional differences between ACLY isoforms. Here, we show that there are no discernible differences in enzymatic activity or stability between isoforms or phosphomutants of ACLY in vitro. Similarly, both isoforms and phosphomutants were able to rescue ACLY functions, including fatty acid synthesis and bulk histone acetylation, when re-expressed in Acly knockout cells. Deletion of Acly exon 14 in mice did not overtly impact development or metabolic physiology, nor did it attenuate tumor burden in a genetic model of intestinal cancer. Notably, expression of epithelial splicing regulatory protein 1 (ESRP1) is highly correlated with ACLY PSI. We report that ACLY splicing is regulated by ESRP1. In turn, both ESRP1 expression and ACLY PSI are correlated with specific immune signatures in tumors. Despite these intriguing patterns of ACLY splicing in healthy and cancer tissues, functional differences between the isoforms remain elusive.

11.
J Infect Dev Ctries ; 18(4): 495-500, 2024 Apr 30.
Article in English | MEDLINE | ID: mdl-38728633

ABSTRACT

INTRODUCTION: After the Coronavirus Disease 2019 pandemic, a high number of cases and severe dengue in children were reported in some provinces in the south of Vietnam. This study aimed to determine the distribution of dengue virus serotypes and their correlation with demographic factors, disease severity, clinical manifestations, and laboratory findings. METHODOLOGY: This study employed a cross-sectional design. Ninety-six dengue-infected children admitted to Can Tho Children's Hospital between October 2022 and March 2023 were included. Confirmation of dengue infection was achieved through the real-time polymerase chain reaction (RT-PCR). RESULTS: Among the identified serotypes, DENV-2 accounted for the highest proportion (71.87%), followed by DENV-1 (23.96%), and DENV-4 (4.17%). DENV-3 was not detected. No significant demographic, disease severity, or laboratory differences were observed among the identified dengue serotypes. However, DENV-2 was associated with a higher occurrence of mucous membrane hemorrhages and gastrointestinal bleeding compared to other serotypes. CONCLUSIONS: Although DENV-2 was the most prevalent serotype responsible for dengue in children in southern Vietnam, it did not lead to more severe cases compared to other serotypes. This finding is crucial for evaluating the illness's prognosis.


Subject(s)
Dengue Virus , Serogroup , Severe Dengue , Humans , Vietnam/epidemiology , Severe Dengue/epidemiology , Severe Dengue/virology , Cross-Sectional Studies , Male , Dengue Virus/classification , Dengue Virus/genetics , Dengue Virus/isolation & purification , Female , Child , Child, Preschool , Adolescent , Infant , Severity of Illness Index
12.
Cureus ; 16(4): e57961, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38738097

ABSTRACT

We present the case of a 13-year-old male with sickle cell disease (SCD) who presented to the emergency department with a severe headache secondary to calvarial infarcts with associated epidural and subgaleal hematomas. This case was complicated by external compression of the superior sagittal sinus by the hematomas as seen on magnetic resonance imaging. Management included supportive treatment of pain and swelling. This case emphasizes skull infarctions with associated hematomas as a possible differential diagnosis for patients with SCD presenting with headaches and scalp swellings.

13.
J Craniofac Surg ; 2024 May 13.
Article in English | MEDLINE | ID: mdl-38738880

ABSTRACT

STUDY DESIGN: Cephalometric scans were compared before and after surgery to assess the degree of correction. Correlations between skeletal movements and survey outcomes were determined using multivariate regression analysis. OBJECTIVE: This study aims to identify relationships between subjective observer-reported improvements in esthetics and emotional appearance with specific surgical movements. METHODS: Ten patients at a single tertiary institution (average age: 18.1 ± 0.8), 9 males and 1 female, underwent orthognathic repair and had comprehensive cephalometric records. Standardized anterior posterior and lateral pre and postoperative photographs of patients were included in a survey to clinicians to assess noncognitive domains on a Likert Scale (1-10). CLEFT-Q was administered to gauge patient satisfaction in categories of appearance, speech, and quality of life. RESULTS: Per clinicians, multiple domains increased including facial attractiveness (4.1 ± 0.7 versus 7.3 ± 0.7, P < 0.001), friendliness (4.5 ± 0.4 versus 7.3 ± 0.5, P < 0.001), confidence (4.1 ± 0.4 versus 7.1 ± 0.4, P < 0.001), and recommendation for surgery decreased (8.9 ± 0.1 versus 3.6 ± 0.5, P < 0.001). Speech distress decreased with increased SNA and convexity, whereas Psychological and Social scores decreased with an increased ANB. Functional eating and drinking scores increased with maxillary depth. CONCLUSIONS: Orthognathic surgery improves many noncognitive domains in patients with cleft lip and palate as assessed by both patients and clinicians on all aspects of facial attractiveness and perception. These findings demonstrate objective bases of skeletal adjustments for perceived improvements in facial appearance and emotion.

14.
Int J Clin Pharm ; 2024 May 11.
Article in English | MEDLINE | ID: mdl-38734867

ABSTRACT

BACKGROUND: Medication errors significantly compromise patient safety in emergency departments. Although previous studies have investigated the prevalence of these errors in this setting, results have varied widely. AIM: The aim was to report pooled data on the prevalence and severity of medication errors in emergency departments, as well as the proportion of patients affected by these errors. METHOD: Systematic searches were conducted in Embase, PubMed, and the Cochrane Library from database inception until June 2023. Studies provided numerical data on medication errors within emergency departments were eligible for inclusion. Random-effects meta-analysis was employed to pool the prevalence of medication errors, the proportion of patients experiencing these errors, and the error severity levels. Heterogeneity among studies was assessed using the I2 statistic and Cochran's Q test. RESULTS: Twenty-four studies met the inclusion criteria. The meta-analysis gave a pooled prevalence of medication errors in emergency departments of 22.6% (95% Confidence Interval [CI] 19.2-25.9%, I2 = 99.9%, p < 0.001). The estimated proportion of patients experiencing medication errors was 36.3% (95% CI 28.3-44.3%, I2 = 99.8%, p < 0.001). Of these errors, 42.6% (95% CI 5.0-80.1%) were potentially harmful but not life-threatening, while no-harm errors accounted for 57.3% (95% CI 14.1-100.0%). CONCLUSION: The prevalence of medication errors, particularly those potentially harmful, underscores potential safety issues in emergency departments. It is imperative to develop and implement effective interventions aimed at reducing medication errors and enhancing patient safety in this setting.

15.
J Craniofac Surg ; 2024 May 14.
Article in English | MEDLINE | ID: mdl-38743287

ABSTRACT

OBJECTIVE: Postoperative nasal stents (NSs) are used to improve esthetic outcomes after primary or secondary cleft lip repair (CLR). Prior studies have utilized anthropometric measurements or physician assessment to determine the efficacy of NS, but data on caregiver-reported outcomes is limited. This study aims to assess caregiver compliance and satisfaction with postoperative NS. METHODS: The authors designed a survey to collect parent-reported postoperative NS usage outcomes. Parents of infants with cleft lip (CL) who used postoperative NS after primary CLR were approached through social media to complete the survey. Data were analyzed to determine factors impacting compliance, satisfaction, and parent-reported outcomes. RESULTS: Eighty-five parents completed the questionnaire, and 60% reported noncompliance with NS. Parents with male children (odds ratio: 5.08, P = 0.019) and patients with incomplete CL (odds ratio: 5.72, P = 0.006) were more likely to be non-compliant with NS for over a week. Complete CL and use of presurgical molding therapy were each associated with better overall experience with postoperative NS (P = 0.002 and P = 0.037), higher appearance ratings (P = 0.005 and P = 0.0008), and greater satisfaction with nostril shape after surgery (P = 0.016 and P = 0.001). CONCLUSIONS: Despite limited literature related to caregiver-reported outcomes after postoperative NS for primary CLR, the authors' results align with what has been published regarding this topic. These results can help guide surgeons in counseling patients preoperatively. Larger, multi-institutional studies are needed to better delineate and address factors associated with compliance and satisfaction after NS therapy.

16.
Mult Scler J Exp Transl Clin ; 10(2): 20552173241252571, 2024.
Article in English | MEDLINE | ID: mdl-38756414

ABSTRACT

Background: Low-intensity repetitive transcranial magnetic stimulation (rTMS), delivered as a daily intermittent theta burst stimulation (iTBS) for four consecutive weeks, increased the number of new oligodendrocytes in the adult mouse brain. Therefore, rTMS holds potential as a remyelinating intervention for people with multiple sclerosis (MS). Objective: Primarily to determine the safety and tolerability of our rTMS protocol in people with MS. Secondary objectives include feasibility, blinding and an exploration of changes in magnetic resonance imaging (MRI) metrics, patient-reported outcome measures (PROMs) and cognitive or motor performance. Methods: A randomised (2:1), placebo controlled, single blind, parallel group, phase 1 trial of 20 rTMS sessions (600 iTBS pulses per hemisphere; 25% maximum stimulator output), delivered over 4-5 weeks. Twenty participants were randomly assigned to 'sham' (n = 7) or active rTMS (n = 13), with the coil positioned at 90° or 0°, respectively. Results: Five adverse events (AEs) including one serious AE reported. None were related to treatment. Protocol compliance was high (85%) and blinding successful. Within participant MRI metrics, PROMs and cognitive or motor performance were unchanged over time. Conclusion: Twenty sessions of rTMS is safe and well tolerated in a small group of people with MS. The study protocol and procedures are feasible. Improvement of sham is warranted before further investigating safety and efficacy.

17.
Nanoscale ; 2024 May 24.
Article in English | MEDLINE | ID: mdl-38787696

ABSTRACT

Hydrophobic drugs, while designed to interact with specific receptors or enzymes located in lipid-rich cell membranes, often face challenges of limited bioavailability and insufficient circulation time due to their insolubility in aqueous environments. One plausible pathway to increase their blood circulation time is to load these drugs into biocompatible and hydrophilic carriers to enhance their uptake. In this study, mesoporous silica (mSiO2) nanocarriers of various morphologies (including cubes, capsules, and spheres) were synthesized. These nanocarriers were then surface-functionalized with alkyl chain hydrocarbons, specifically octadecyl-trimethoxysilane, (OCH3)3Si(CH2)17CH3, to render them hydrophobic. The resulting nanocarriers (((OCH3)3Si(CH2)17CH3)@mSiO2) showed up to 80% uptake for hydrophobic drugs. However, a significant drawback was observed as most of the drugs were prone to uncontrollable release within 6 h. This challenge of premature drug release was successfully mitigated by effectively sealing the drug-loaded nanocarriers with a pH-sensitive lipid overlayer. The lipid-coated nanocarriers prolonged drug containment and sustained release up to 72 h, compared to 6 h for uncoated nanocarriers, thereby facilitating longer blood circulation times. Moreover, the shape and size of nanocarriers were found to influence both drug entrapment capacity and release behavior with cubic forms exhibiting superior loading capacity due to higher surface area and porosity. Additionally, it was observed that the molecular weight and chemical structure of the drug molecules played a crucial role in determining their uptake and release profiles. Furthermore, the influence of different morphologies of nanocarriers on cell uptake and cytotoxicity in immune cells was elucidated. These findings underscore the importance of nanocarrier morphology and drug properties to enhance loading capacities and controlled release profiles, for designing drug delivery systems tailored for hydrophobic drugs.

18.
Inorg Chem ; 63(21): 9763-9770, 2024 May 27.
Article in English | MEDLINE | ID: mdl-38739043

ABSTRACT

The delafossites are a class of layered metal oxides that are notable for being able to exhibit optical transparency alongside an in-plane electrical conductivity, making them promising platforms for the development of transparent conductive oxides. Pressure-induced polymorphism offers a direct method for altering the electrical and optical properties in this class, and although the copper delafossites have been studied extensively under pressure, the silver delafossites remain only partially studied. We report two new high-pressure polymorphs of silver ferrite delafossite, AgFeO2, that are stabilized above ∼6 and ∼14 GPa. In situ X-ray diffraction and vibrational spectroscopy measurements are used to examine the structural changes across the two phase transitions. The high-pressure structure between 6 and 14 GPa is assigned as a monoclinic C2/c structure that is analogous to the high-pressure phase reported for AgGaO2. Nuclear resonant forward scattering reveals no change in the spin state or valence state at the Fe3+ site up to 15.3(5) GPa.

19.
Res Sq ; 2024 May 07.
Article in English | MEDLINE | ID: mdl-38766151

ABSTRACT

Between 2010 and 2011, stakeholders implemented a multi-faceted community-based intervention in response to the escalating issue of uncontrolled hypertension in Hung Yen province, Vietnam. This initiative integrated expanded community health worker services, home blood pressure self-monitoring, and a unique "storytelling intervention" into routine clinical care. From the limited societal perspective, our study evaluates the cost-effectiveness of this intervention using a Markov model with a one-year cycle over a lifetime horizon. The analysis, based on a cohort of 671 patients, reveals a lifetime incremental cost of approximately VND 90.37 million (USD 3,930) per quality-adjusted life year (QALY) gained. With a willingness to pay at three times GDP (VND 259.2 million per QALY), the intervention proves cost-effective 80% of the time. This research underscores the potential of the community-based approach to effectively control hypertension, offering valuable insights into its broader implications for public health.

20.
Ann Neurol ; 2024 May 15.
Article in English | MEDLINE | ID: mdl-38747498

ABSTRACT

OBJECTIVES: Due to increased gene dose for the amyloid precursor protein (APP), elderly adults with Down syndrome (DS) are at a markedly increased risk of Alzheimer's disease (AD), known as DS-AD. How the increased APP gene dose acts and which APP products are responsible for DS-AD is not well understood, thus limiting strategies to target pathogenesis. As one approach to address this question, we used a novel class of γ-secretase modulators that promote γ-site cleavages by the γ-secretase complex, resulting in lower levels of the Aß42 and Aß40 peptides. METHODS: Ts65Dn mice, which serve as a model of DS, were treated via oral gavage with 10 mg/kg/weekday of BPN15606 (a potent and novel pyridazine-containing γ-secretase modulators). Treatment started at 3 months-of-age and lasted for 4 months. RESULTS: Demonstrating successful target engagement, treatment with BPN15606 significantly decreased levels of Aß40 and Aß42 in the cortex and hippocampus; it had no effect on full-length APP or its C-terminal fragments in either 2 N or Ts65Dn mice. Importantly, the levels of total amyloid-ß were not impacted, pointing to BPN15606-mediated enhancement of processivity of γ-secretase. Additionally, BPN15606 rescued hyperactivation of Rab5, a protein responsible for regulating endosome function, and normalized neurotrophin signaling deficits. BPN15606 treatment also normalized the levels of synaptic proteins and tau phosphorylation, while reducing astrocytosis and microgliosis, and countering cognitive deficits. INTERPRETATION: Our findings point to the involvement of increased levels of Aß42 and/or Aß40 in contributing to several molecular and cognitive traits associated with DS-AD. They speak to increased dosage of the APP gene acting through heightened levels of Aß42 and/or Aß40 as supporting pathogenesis. These findings further the interest in the potential use of γ-secretase modulators for treating and possibly preventing AD in individuals with DS. ANN NEUROL 2024.

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