bluuebunny/crossref_metadata_2025 huggingface dataset:
MDM2: current research status and prospects of tumor treatment
Authors: Yao Yumei , Zhang Qian , Li Zhi , Zhang Hushan
Published: May 2024

Mousedouble minute 2 (MDM2) is one of the molecules activated by p53 and plays an important role in the regulation of p53. MDM2 is generally believed to function as a negative regulator of p53 by facilitating its ubiquitination and subsequent degradation. Consequently, blocked p53 activity often fails in damaged cells to undergo cell cycle arrest or apoptosis. Given that around 50% of human cancers involve the inactivation of p53 through genetic mutations, and directly targeting p53 through drug development has limited feasibility, targeting molecular regulation related to p53 has great potential and has become a research hotspot. For example, developing drugs that target the interaction between p53 and MDM2. Such drugs aim to reactivate p53 by targeting either MDM2 binding or p53 phosphorylation. Researchers have identified various compounds that can serve as inhibitors, either by directly binding to MDM2 or by modifying p53 through phosphorylation. Furthermore, a significant correlation exists between the expression of MDM2 in tumors and the effectiveness of immunotherapy, predominantly in the context of immune checkpoint inhibition. This review presents a comprehensive overview of the molecular characteristics of MDM2 and the current state of research on MDM2-targeting inhibitors. It includes a review of the impact of MDM2 targeting on the efficacy of immunotherapy, providing guidance and direction for the development of drugs targeting the p53-MDM2 interaction and optimization of immunotherapy.
Analysing the outbreaks of leptospirosis after floods in Kerala, India
Authors: Ifejube Oluwafemi John , Kuriakose Sekhar L. , Anish T. S. , van Westen Cees , Blanford Justine I.
Published: May 2024

A growing number of studies have linked the incidence of leptospirosis with the occurrence of flood events. Nevertheless, the interaction between flood and leptospirosis has not been extensively studied to understand the influence of flood attributes in inducing new cases. This study reviews leptospirosis cases in relation to multiple flood occurrences in Kerala, India. Leptospirosis data were obtained for three years: 2017 (non-flood year) and two years with flooding—2018 (heavy flooding) and 2019 (moderate flooding). We considered the severity of flood events using the discharge, duration and extent of each flooding event and compared them with the leptospirosis cases. The distribution of cases regarding flood discharge and duration was assessed through descriptive and spatiotemporal analyses, respectively. Furthermore, cluster analyses and spatial regression were completed to ascertain the relationship between flood extent and the postflood cases. This study found that postflood cases of leptospirosis can be associated with flood events in space and time. The total cases in both 2018 and 2019 increased in the post-flood phase, with the increase in 2018 being more evident. Unlike the 2019 flood, the flood of 2018 is a significant spatial indicator for postflood cases. Our study shows that flooding leads to an increase in leptospirosis cases, and there is stronger evidence for increased leptospirosis cases after a heavy flood event than after a moderate flooding event. Flood duration may be the most important factor in determining the increase in leptospirosis infections.
High-dose naloxone formulations are not as essential as we thought
Authors: Lemen Paige M. , Garrett Daniel P. , Thompson Erin , Aho Megan , Vasquez Christina , Park Ju Nyeong
Published: May 2024

Naloxone is an effective FDA-approved opioid antagonist for reversing opioid overdoses. Naloxone is available to the public and can be administered through intramuscular (IM), intravenous (IV), and intranasal spray (IN) routes. Our literature review investigates the adequacy of two doses of standard IM or IN naloxone in reversing fentanyl overdoses compared to newer high-dose naloxone formulations. Moreover, our initiative incorporates the experiences of people who use drugs, enabling a more practical and contextually-grounded analysis. The evidence indicates that the vast majority of fentanyl overdoses can be successfully reversed using two standard IM or IN dosages. Exceptions include cases of carfentanil overdose, which necessitates ≥ 3 doses for reversal. Multiple studies documented the risk of precipitated withdrawal using ≥ 2 doses of naloxone, notably including the possibility of recurring overdose symptoms after resuscitation, contingent upon the half-life of the specific opioid involved. We recommend distributing multiple doses of standard IM or IN naloxone to bystanders and educating individuals on the adequacy of two doses in reversing fentanyl overdoses. Individuals should continue administration until the recipient is revived, ensuring appropriate intervals between each dose along with rescue breaths, and calling emergency medical services if the individual is unresponsive after two doses. We do not recommend high-dose naloxone formulations as a substitute for four doses of IM or IN naloxone due to the higher cost, risk of precipitated withdrawal, and limited evidence compared to standard doses. Future research must take into consideration lived and living experience, scientific evidence, conflicts of interest, and the bodily autonomy of people who use drugs.
PPAR-γ agonists reactivate the ALDOC-NR2F1 axis to enhance sensitivity to temozolomide and suppress glioblastoma progression
Authors: Chang Yu-Chan , Chan Ming-Hsien , Li Chien-Hsiu , Chen Chi-Long , Tsai Wen-Chiuan , Hsiao Michael
Published: May 2024

Glioblastoma (GBM) is a type of brain cancer categorized as a high-grade glioma. GBM is characterized by limited treatment options, low patient survival rates, and abnormal serotonin metabolism. Previous studies have investigated the tumor suppressor function of aldolase C (ALDOC), a glycolytic enzyme in GBM. However, it is unclear how ALDOC regulates production of serotonin and its associated receptors, HTRs. In this study, we analyzed ALDOC mRNA levels and methylation status using sequencing data and in silico datasets. Furthermore, we investigated pathways, phenotypes, and drug effects using cell and mouse models. Our results suggest that loss of ALDOC function in GBM promotes tumor cell invasion and migration. We observed that hypermethylation, which results in loss of ALDOC expression, is associated with serotonin hypersecretion and the inhibition of PPAR-γ signaling. Using several omics datasets, we present evidence that ALDOC regulates serotonin levels and safeguards PPAR-γ against serotonin metabolism mediated by 5-HT, which leads to a reduction in PPAR-γ expression. PPAR-γ activation inhibits serotonin release by HTR and diminishes GBM tumor growth in our cellular and animal models. Importantly, research has demonstrated that PPAR-γ agonists prolong animal survival rates and increase the efficacy of temozolomide in an orthotopic brain model of GBM. The relationship and function of the ALDOC-PPAR-γ axis could serve as a potential prognostic indicator. Furthermore, PPAR-γ agonists offer a new treatment alternative for glioblastoma multiforme (GBM).
Acacetin alleviates autoimmune myocarditis by regulating CD4+ T cell mitochondrial respiration
Authors: Lu Yang , Wu Yu-Wei , Pu Jiu , Wu Qiong-Feng , Dong Qian , Zhao Ning , Li Gui-Rong , Du Yi-Mei
Published: May 2024

Background

Myocarditis refers to an autoimmune inflammatory response of the myocardium with characterization of self-reactive CD4+ T cell activation, which lacks effective treatment and has a poor prognosis. Acacetin is a natural flavonoid product that has been reported to have anti-inflammatory effects. However, acacetin has not been investigated in myocarditis.

Methods

Oral acacetin treatment was administered in an experimental autoimmune myocarditis model established with myosin heavy chain-alpha peptide. Echocardiography, pathological staining, and RT-qPCR were used to detect cardiac function, myocardial injury, and inflammation levels. Flow cytometry was utilized to detect the effect of acacetin on CD4+ T cell function. RNA-seq, molecular docking, and microscale thermophoresis (MST) were employed to investigate potential mechanisms. Seahorse analysis, mitoSOX, JC-1, and mitotracker were utilized to detect the effect of acacetin on mitochondrial function.

Results

Acacetin attenuated cardiac injury and fibrosis as well as heart dysfunction, and reduced cardiac inflammatory cytokines and ratio of effector CD4+ T and Th17 cells. Acacetin inhibited CD4+ T cell activation, proliferation, and Th17 cell differentiation. Mechanistically, the effects of acacetin were related to reducing mitochondrial complex II activity thereby inhibiting mitochondrial respiration and mitochondrial reactive oxygen species in CD4+ T cells.

Conclusion

Acacetin may be a valuable therapeutic drug in treating CD4+ T cell-mediated myocarditis.

Graphical Abstract
Neuropsychological profile associated with KAT6A syndrome: Emergent genotype-phenotype trends
Authors: Ng Rowena , Kalinousky Allison J , Harris Jacqueline
Published: May 2024

Background

KAT6A (Arboleda-Tham) syndrome is a Mendelian disorder of the epigenetic machinery caused by pathogenic variants in the lysine acetyltransferase 6 A (KAT6A) gene. Intellectual disability and speech/language impairment (e.g., minimally verbal) are common features of the disorder, with late-truncating variants associated with a more severe form of intellectual disability. However, much of the cognitive phenotype remains elusive given the dearth of research.

Participants and methods

This study examined non-verbal and social skills of 15 individuals with molecularly-confirmed diagnoses of KAT6A syndrome (Mean age = 10.32 years, SD = 4.12). Participants completed select subtests from the DAS-II, the NEPSY-II, and the Beery Buktenica Developmental Test of Visual Motor Integration 6th Edition, and their caregivers completed an assortment of behavior rating inventories.

Results

Findings suggest global cognitive impairment with nonverbal cognition scores similar to those for receptive language. Autism-related features, particularly restricted interests and repetitive behaviors, and broad adaptive deficits were common in our sample juxtaposed with a relatively strong social drive and low frequency of internalizing and externalizing behavioral problems. A general trend of lower performance scores on nonverbal and receptive language measures was observed among those with protein-truncating variants vs. missense variants; however, no effect was observed on caregiver rating inventories of daily behaviors. Late and early truncating variants yielded comparable neuropsychological profiles.

Conclusions

Overall, study results show the cognitive phenotype of KAT6A syndrome includes equally impaired nonverbal cognition and receptive language functioning, paired with relatively intact social drive and strengths in behavior regulation. Emergent genotype-phenotype correlations suggest cognition may be more affected in protein-truncating than missense mutations although similar neurobehavioral profiles were observed.
A 360-degree perspective on adeno-associated virus (AAV)-based gene therapy for haemophilia: Insights from the physician, the nurse and the patient
Authors: Miesbach Wolfgang , Mulders Greta , Breederveld Daan , Pinachyan Karen , Le Quellec Sandra , Pabinger Ingrid
Published: May 2024

Background

Adeno-associated virus (AAV)-based gene therapy for haemophilia has advanced substantially in the last 13 years; recently, three products have received approvals from regulatory authorities. Although the impact on quality of life seems promising, some limitations remain, such as the presence of pre-existing anti-AAV neutralising antibodies and the occurrence of hepatotoxicity. This review follows the CSL Behring-sponsored symposium at the 27th Congress of the European Hematology Association (EHA) 2022 that examined the haemophilia gene therapy process from a 360-degree multidisciplinary perspective. Here, the faculty (haematologist, nurse and haemophilia patient) summarised their own viewpoints from the symposium, with the aim of highlighting the key considerations required to engage with gene therapy effectively, for both patients and providers, as well as the importance of multidisciplinary collaboration, including with industry.

Results

When considering these new therapies, patients face a complex decision-making process, which includes whether gene therapy is right for them at their current stage of life. The authors agreed that collaboration and tailored education across the multidisciplinary team (including patients and their carers/families), starting early in the process and continuing throughout the long-term follow-up period, is key for the success of gene therapy. Additionally, patient expectations, which may surround eligibility, follow-up requirements and treatment outcomes, should be continually explored. During these ongoing discussions, transparent communication of the unknown factors, such as anticipated clotting factor levels, long-term factor expression and safety, and psychological changes, is critical. To ensure efficiency and comprehensiveness, clearly‑defined protocols should outline the whole process, which should include the recording and management of long-term effects.

Conclusion

In order to engage effectively, both patients and providers should be familiar with these key considerations prior to their involvement with the haemophilia gene therapy process. The future after the approval of haemophilia gene therapies remains to be seen and real-world evidence is eagerly awaited.
Ethanol embolization of arteriovenous malformations in the buttock: ten-year experiences in diagnoses and treatment options
Authors: Shen Yuchen , Wang Deming , Fan Xindong , Zheng Lianzhou , Su Lixin , Yang Xitao
Published: May 2024

Background

Clinically, arteriovenous malformations in the buttocks (bAVMs) are extremely rare. Our study aimed to evaluate the efficacy and safety of ethanol embolotherapy in managing bAVMs.

Results

A total of 32 patients with bAVMs (14 females and 18 males) from 2012 to 2021 were included in this study. All patients underwent complete clinical and imaging examinations. Further, the AVMs lesions were analyzed according to Schöbinger staging and Yakes classification. Each patient had undergone a multistage ethanol embolization. The amelioration of clinical symptoms and devascularization on angiography were evaluated at regular follow-ups. In the present cohort, the 11–20 age group had the most patients (15/32; 46.88%). A total of 124 embolization procedures were performed (average 3.88 procedures per patient), and the average dose of absolute ethanol was 18.96 mL per procedure. Thirteen patients with dominant draining veins underwent additional coil deployment before ethanol embolization (13/32; 40.63%). During follow-ups, clinical improvement was found in 23 of 27 who presented with a pulsating mass (85.19%), 17 of 20 with abnormal local skin temperature (85%), 5 of 6 with bleeding (83.33%), and 5 of 5 patients treated for pain (100%). More than 75% angiographic devascularization was achieved in 18 patients (18/32; 56.25%). Finally, 12 out of 13 patients (92.31%) reduced from Schöbinger Stage III to a lower grade, and ten patients exhibited a complete response (10/32; 31.23%). There was a single serious complication of local necrosis, while neither paranesthesia nor infection was observed postoperatively.

Conclusions

Ethanol embolization assisted with coils can treat bAVMs effectively and safely. The Yakes classification contributed to the optimal ethanol embolotherapy of bAVMs.
Metabolic engineering of Saccharomyces cerevisiae for the biosynthesis of a fungal pigment from the phytopathogenic fungus Cladosporium phlei
Authors: Gwon Yeji , So Kum-Kang , Chun Jeesun , Kim Dae-Hyuk
Published: May 2024

Background

Cladosporium phlei is a phytopathogenic fungus that produces a pigment called phleichrome. This fungal perylenequinone plays an important role in the production of a photosensitizer that is a necessary component of photodynamic therapy. We applied synthetic biology to produce phleichrome using Saccharomyces cerevisiae.

Results

The gene Cppks1, which encodes a non-reducing polyketide synthase (NR-PKS) responsible for the biosynthesis of phleichrome in C. phlei, was cloned into a yeast episomal vector and used to transform S. cerevisiae. In addition, a gene encoding a phosphopantetheinyl transferase (PPTase) of Aspergillus nidulans was cloned into a yeast integrative vector and also introduced into S. cerevisiae for the enzymatic activation of the protein product of Cppks1. Co-transformed yeasts were screened on a leucine/uracil-deficient selective medium and the presence of both integrative as well as episomal recombinant plasmids in the yeast were confirmed by colony PCR. The episomal vector for Cppks1 expression was so dramatically unstable during cultivation that most cells lost their episomal vector rapidly in nonselective media. This loss was also observed to a less degree in selective media. This data strongly suggests that the presence of the Cppks1 gene exerts a significant detrimental effect on the growth of transformed yeast cells and that selection pressure is required to maintain the Cppks1-expressing vector. The co-transformants on the selective medium showed the distinctive changes in pigmentation after a period of prolonged cultivation at 20 °C and 25 °C, but not at 30 °C. Furthermore, thin layer chromatography (TLC) revealed the presence of a spot corresponding with the purified phleichrome in the extract from the cells of the co-transformants. Liquid chromatography (LC/MS/MS) verified that the newly expressed pigment was indeed phleichrome.

Conclusion

Our results indicate that metabolic engineering by multiple gene expression is possible and capable of producing fungal pigment phleichrome in S. cerevisiae. This result adds to our understanding of the characteristics of fungal PKS genes, which exhibit complex structures and diverse biological activities.
Single-cell 3D genome structure reveals distinct human pluripotent states
Authors: Li Niannian , Jin Kairang , Liu Bin , Yang Mingzhu , Shi PanPan , Heng Dai , Wang Jichang , Liu Lin
Published: May 2024

Background

Pluripotent states of embryonic stem cells (ESCs) with distinct transcriptional profiles affect ESC differentiative capacity and therapeutic potential. Although single-cell RNA sequencing has revealed additional subpopulations and specific features of naive and primed human pluripotent stem cells (hPSCs), the underlying mechanisms that regulate their specific transcription and that control their pluripotent states remain elusive.

Results

By single-cell analysis of high-resolution, three-dimensional (3D) genomic structure, we herein demonstrate that remodeling of genomic structure is highly associated with the pluripotent states of human ESCs (hESCs). The naive pluripotent state is featured with specialized 3D genomic structures and clear chromatin compartmentalization that is distinct from the primed state. The naive pluripotent state is achieved by remodeling the active euchromatin compartment and reducing chromatin interactions at the nuclear center. This unique genomic organization is linked to enhanced chromatin accessibility on enhancers and elevated expression levels of naive pluripotent genes localized to this region. In contradistinction, the primed state exhibits intermingled genomic organization. Moreover, active euchromatin and primed pluripotent genes are distributed at the nuclear periphery, while repressive heterochromatin is densely concentrated at the nuclear center, reducing chromatin accessibility and the transcription of naive genes.

Conclusions

Our data provide insights into the chromatin structure of ESCs in their naive and primed states, and we identify specific patterns of modifications in transcription and chromatin structure that might explain the genes that are differentially expressed between naive and primed hESCs. Thus, the inversion or relocation of heterochromatin to euchromatin via compartmentalization is related to the regulation of chromatin accessibility, thereby defining pluripotent states and cellular identity.
Retraction Note: Hierarchical energy-saving routing algorithm using fuzzy logic in wireless sensor networks
Authors: Wang Dan , Wu Qing , Hu Ming
Published: May 2024

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1186/s13635-023-00144-1.
Existence of periodic solutions for a class of $(\phi _{1},\phi _{2})$-Laplacian difference system with asymptotically $(p,q)$-linear conditions
Authors: Deng Hai-yun , Lin Xiao-yan , He Yu-bo
Published: May 2024

In this paper, we consider a $(\phi _{1},\phi _{2})$
(

ϕ
1

,

ϕ
2

)
-Laplacian system as follows: $$\begin{aligned} \textstyle\begin{cases} \Delta \phi _{1} (\Delta u(t-1) )+\nabla _{u} F(t,u(t),v(t))=0, \\ \Delta \phi _{2} (\Delta v(t-1) )+\nabla _{v} F(t,u(t),v(t))=0, \end{cases}\displaystyle \end{aligned}$$

{

Δ

ϕ
1

(
Δ
u
(
t
−
1
)
)
+

∇
u

F
(
t
,
u
(
t
)
,
v
(
t
)
)
=
0
,

Δ

ϕ
2

(
Δ
v
(
t
−
1
)
)
+

∇
v

F
(
t
,
u
(
t
)
,
v
(
t
)
)
=
0
,

where $F(t,u(t),v(t))=-K(t,u(t),v(t))+W(t,u(t),v(t))$
F
(
t
,
u
(
t
)
,
v
(
t
)
)
=
−
K
(
t
,
u
(
t
)
,
v
(
t
)
)
+
W
(
t
,
u
(
t
)
,
v
(
t
)
)
is T-periodic in t. By using the mountain pass theorem, we obtain that the $(\phi _{1},\phi _{2})$
(

ϕ
1

,

ϕ
2

)
-Laplacian system has at least one periodic solution if W is asymptotically $(p,q)$
(
p
,
q
)
-linear at infinity. Our results improve and extend some known works.
Study protocol for a randomized controlled trial of supportive parents – coping kids (SPARCK)—a transdiagnostic and personalized parent training intervention to prevent childhood mental health problems
Authors: Tømmerås T. , Backer-Grøndahl A. , Høstmælingen A. , Laland H. , Gomez M. B. , Apeland A. , Karlsson L. R. A. , Grønlie A. A. , Torsvik S. , Bringedal G. E. ,   Advisory Consortium, Monica Aas , Fisher Phillip Andrew , Gardner Frances , Kjøbli John , Malmberg-Heimonen Ira , Nissen-Lie Helene Amundsen
Published: May 2024

Background

To meet the scientific and political call for effective prevention of child and youth mental health problems and associated long-term consequences, we have co-created, tested, and optimized a transdiagnostic preventive parent-training intervention, Supportive parents – coping kids (SPARCK), together with and for the municipal preventive frontline services. The target group of SPARCK is parents of children between 4 and 12 years who display symptoms of anxiety, depression, and/or behavioral problems, that is, indicated prevention. The intervention consists of components from various empirically supported interventions representing different theorical models on parent–child interactions and child behavior and psychopathology (i.e., behavioral management interventions, attachment theory, emotion socialization theory, cognitive-behavioral therapy, and family accommodation intervention). The content and target strategies of SPARCK are tailored to the needs of the families and children, and the manual suggests how the target strategies may be personalized and combined throughout the maximum 12 sessions of the intervention. The aim of this project is to investigate the effectiveness of SPARCK on child symptoms, parenting practices, and parent and child stress hormone levels, in addition to later use of specialized services compared with usual care (UC; eg. active comparison group).

Methods

We describe a randomized controlled effectiveness trial in the frontline services of child welfare, health, school health and school psychological counselling services in 24 Norwegian municipalities. It is a two-armed parallel group randomized controlled effectiveness and superiority trial with 252 families randomly allocated to SPARCK or UC. Assessment of key variables will be conducted at pre-, post-, and six-month follow-up.

Discussion

The current study will contribute with knowledge on potential effects of a preventive transdiagnostic parent-training intervention when compared with UC. Our primary objective is to innovate frontline services with a usable, flexible, and effective intervention for prevention of childhood mental health problems to promote equity in access to care for families and children across a heterogeneous service landscape characterized by variations in available resources, personnel, and end user symptomatology.

Trial registration

ClinicalTrials.gov ID: NTCT05800522
Global research trend and hotspot in the low FODMAP diet: a bibliometric analysis
Authors: Xu Cheng , Song Zhen , Hu Jing-yi , Li Chong-chao , Shen Hong
Published: May 2024

Background

According to national guidelines, a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) is a second-line therapy option for irritable bowel syndrome (IBS) and improves functional intestinal symptoms. Numerous noteworthy results have been published in this field over the past fifteen years. This study aims to analyze the global research trend and hotspot of the low FODMAP diet research, and provide a comprehensive perspective and direction for researchers.

Methods

The Science Citation Index-Expanded of the Web of Science Core Collection (WoSCC) was used to identify low FODMAP diet-related articles and reviews. Three bibliometric programs (CiteSpace, VOSviewer, Scimago Graphic) were utilized to analyze and visualize the annual publications, authors, countries, institutions, journals, citations, and keywords.

Results

In total, 843 documents related to the low FODMAP diet research were published in 227 journals by 3,343 authors in 1,233 institutions from 59 countries. The United States, which was the most engaged nation in international collaboration, had the largest annual production and the fastest growth. The most productive organization was Monash University, and the most fruitful researcher was Gibson PR. Nutrients ranked first in terms of the number of published documents. The article “A diet low in FODMAPs reduces symptoms of irritable bowel syndrome” (Halmos EP, 2014) received the most co-citations. Keywords that appear frequently in the literature mainly involve two main aspects: the clinical efficacy evaluation and mechanism exploration of the low FODMAP diet. The term “gut microbiota” stands out as the most prominent keyword among the burst keywords that have remained prevalent till date.

Conclusion

The restriction stage of the low FODMAP diet is superior to other dietary therapies for IBS in terms of symptom response, but it has a negative impact on the abundance of gut Bifidobacteria and diet quality. Identification of biomarkers to predict response to the low FODMAP diet is of great interest and has become the current research hotspot.
Crowdsourcing RTK: a new GNSS positioning framework for building spatial high-resolution atmospheric maps based on massive vehicle GNSS data
Authors: Xu Hongjin , Chen Xingyu , Ou Jikun , Yuan Yunbin
Published: May 2024

High-quality spatial atmospheric delay correction information is essential for achieving fast integer ambiguity resolution (AR) in precise positioning. However, traditional real-time precise positioning frameworks (i.e., NRTK and PPP-RTK) depend on spatial low-resolution atmospheric delay correction through the expensive and sparsely distributed CORS network. This results in limited public appeal. With the mass production of autonomous driving vehicles, more cost-effective and widespread data sources can be explored to create spatial high-resolution atmospheric maps. In this study, we propose a new GNSS positioning framework that relies on dual base stations, massive vehicle GNSS data, and crowdsourced atmospheric delay correction maps (CAM). The map is easily produced and updated by vehicles equipped with GNSS receivers in a crowd-sourced way. Specifically, the map consists of between-station single-differenced ionospheric and tropospheric delays. We introduce the whole framework of CAM initialization for individual vehicles, on-cloud CAM maintenance, and CAM-augmented user-end positioning. The map data are collected and preprocessed in vehicles. Then, the crowdsourced data are uploaded to a cloud server. The massive data from multiple vehicles are merged in the cloud to update the CAM in time. Finally, the CAM will augment the user positioning performance. This framework forms a beneficial cycle where the CAM’s spatial resolution and the user positioning performance mutually improve each other. We validate the performance of the proposed framework in real-world experiments and the applied potency at different spatial scales. We highlight that this framework is a reliable and practical positioning solution that meets the requirements of ubiquitous high-precision positioning.
Methods and associations of suicidality in Kenyan high school students: clinical and public health implications
Authors: Ndetei David M. , Wasserman Danuta , Mutiso Victoria , Shanley Jenelle R. , Musyimi Christine , Nyamai Pascalyne , Munyua Timothy , Swahn Monica H. , Osborn Tom L. , Johnson Natalie E. , Memiah Peter , Bhui Kamaldeep , Gilbert Sonja , Weisz John R. , Javed Afzal , Sourander Andre
Published: May 2024

Background

Most evidence on suicidal thoughts, plans and attempts comes from Western countries; prevalence rates may differ in other parts of the world.

Aims

This study determined the prevalence of suicidal thoughts, plans and attempts in high school students in three different regional settings in Kenya.

Method

This was a cross-sectional study of 2652 high school students. We asked structured questions to determine the prevalence of various types of suicidality, the methods planned or effected, and participants’ gender, age and form (grade level). We provided descriptive statistics, testing significant differences by chi-squared and Fisher's exact tests, and used logistic regression to identify relationships among different variables and their associations with suicidality.

Results

The prevalence rates of suicidal thoughts, plans and attempts were 26.8, 14.9 and 15.7%, respectively. These rates are higher than those reported for Western countries. Some 6.7% of suicide attempts were not associated with plans. The most common method used in suicide attempts was drinking chemicals/poison (18.8%). Rates of suicidal thoughts and plans were higher for older students and students in urban rather than rural locations, and attempts were associated with female gender and higher grade level – especially the final year of high school, when exam performance affects future education and career prospects.

Conclusion

Suicidal thoughts, plans and attempts are prevalent in Kenyan high school students. There is a need for future studies to determine the different starting points to suicidal attempts, particularly for the significant number whose attempts are not preceded by thoughts and plans.
Predicting patients with dementia most at risk of needing psychiatric in-patient or enhanced community care using routinely collected clinical data: retrospective multi-site cohort study
Authors: London Sabina R. , Chen Shanquan , Sidhom Emad , Lewis Jonathan R. , Wolverson Emma , Cardinal Rudolf N. , Roalf David , Mueller Christoph , Underwood Benjamin R.
Published: May 2024

Background

Dementia is a common and progressive condition whose prevalence is growing worldwide. It is challenging for healthcare systems to provide continuity in clinical services for all patients from diagnosis to death.

Aims

To test whether individuals who are most likely to need enhanced care later in the disease course can be identified at the point of diagnosis, thus allowing the targeted intervention.

Method

We used clinical information collected routinely in de-identified electronic patient records from two UK National Health Service (NHS) trusts to identify at diagnosis which individuals were at increased risk of needing enhanced care (psychiatric in-patient or intensive (crisis) community care).

Results

We examined the records of a total of 25 326 patients with dementia. A minority (16% in the Cambridgeshire trust and 2.4% in the London trust) needed enhanced care. Patients who needed enhanced care differed from those who did not in age, cognitive test scores and Health of the Nation Outcome Scale scores. Logistic regression discriminated risk, with an area under the receiver operating characteristic curve (AUROC) of up to 0.78 after 1 year and 0.74 after 4 years. We were able to confirm the validity of the approach in two trusts that differed widely in the populations they serve.

Conclusions

It is possible to identify, at the time of diagnosis of dementia, individuals most likely to need enhanced care later in the disease course. This permits the development of targeted clinical interventions for this high-risk group.
Targeting KRAS Oncogene for Patients With Colorectal Cancer: A New Step Toward Precision Medicine
Authors: Sahin Ibrahim Halil , Saridogan Turcin , Ayasun Ruveyda , Syed Masood Pasha , Gorantla Vikram , Malhotra Monica , Thomas Roby , Rhee John , Zhang Janie , Hsu Dennis , Singhi Aatur D. , Saeed Anwaar
Published: May 2024

KRAS
mutations are common driver oncogenes associated with the development of several solid tumors.
KRAS
oncogene has been considered a highly challenging target for drug development because of structural features, including the lack of deep groove on its catalytic unit. However, by leveraging cysteine residues, covalent KRAS inhibitors irreversibly trap KRAS G12C mutants in their inactive GDP-bound state. These agents have resulted in significant clinical responses among patients with KRAS G12C-mutant solid tumors, including patients with colorectal cancer (CRC). Other allele-specific inhibitors of
KRAS
oncogene and panKRAS and panRAS inhibitors are also currently being investigated in clinical trials. This review article overviews recent clinical progress on KRAS G12C targeting for the management of patients with KRAS G12C-mutant CRC and provides an update on other RAS targeting approaches. We also discuss the unique biological features of RAS-mutant CRC, which require the combination of KRAS inhibitors and anti-epidermal growth factor receptor therapy, and elaborate on resistance mechanisms and novel therapeutic avenues that may define future treatment paradigms of patients with RAS-mutant CRC.
Generation of near-circularly polarized high-order harmonics in two-color cross-linearly polarized laser fields
Authors: Li Z. A. , Huo X. X. , Cheng C. C. , Liu X. S.
Published: May 2024

We investigate theoretically the ellipticity of the high-order harmonic generation from the molecule

by utilizing two-color cross-linearly polarized laser fields. A significant region of the large ellipticity can be achieved by adjusting the crossing angle and the relative phase between the two laser fields. By controlling the short trajectory, we can obtain the smoother harmonic spectrum. The minimum value observed in the plateau region can be attributed to the two-center interference of the molecule. Furthermore, we investigate the contribution of the two-center interference to the ellipticity of HHG. The underlying physical mechanisms of the ellipticity can be demonstrated by the phase difference and amplitude difference of the x and y components of the harmonics. As a result, we synthesized an isolated attosecond pulse with an ellipticity of 0.98.
Membrane protein clustering from tension and multibody interactions
Authors: Fournier Jean-Baptiste
Published: May 2024

The point-curvature model for membrane protein inclusions is shown to capture multibody interactions very well. Using this model, we find that the interplay between membrane tension and multibody interactions results in a collective attraction of oppositely curved inclusions tending to form antiferromagnetic structures with a square lattice. This attraction can produce a phase separation between curved and non-curved proteins, resulting in the clustering of curved proteins. We also show that the many-body repulsion between identical curved proteins is enhanced by membrane tension. This can lead to the dissolution of clusters stabilized by short-range forces when the tension is increased. These new phenomena are biologically relevant and could be investigated experimentally.
Contrasting Bone Profiles in PCOS Are Related to BMI: A Systematic Review and Meta-analysis
Authors: Rissetti Graziela , Piovezan Julia Mottecy , Premaor Melissa Orlandin , Comim Fabio Vasconcellos
Published: May 2024

Context

Controversial results have emerged regarding whether polycystic ovary syndrome (PCOS) is protective or increases the risk of bone frailty.

Objective

This study investigated whether the PCOS condition affects bone parameters of premenopausal women. This is an update for a previous meta-analysis published in 2019.

Data Sources

We searched MEDLINE and Embase.

Study Selection

Studies were considered eligible for the update if published in English between October 1, 2018, and December 31, 2023. The diagnosis of PCOS should be based on National Institutes of Health criteria, the Rotterdam Consensus, Androgen Excess & PCOS Society criteria, or International Classification of Diseases codes in women over 18 years old. Only records with the Newcastle-Ottawa Scale ≥ 6 were selected for data extraction.

Data Extraction

Data were extracted by 2 independent reviewers.

Data Synthesis

We identified 31 studies that met the inclusion criteria for qualitative analysis from 3322 studies in the whole period (1990-2023). Overall, cross-sectional studies included 1822 individuals with PCOS and 1374 controls, while cohort studies incorporated 30 305 women with PCOS and 10,1907 controls. Contrasting profiles emerged after stratification using a body mass index (BMI) cutoff of 27 kg/m2. Individuals with PCOS and a BMI <27 kg/m2 exhibited lower vertebral and nonvertebral bone density, reduced bone turnover marker (osteocalcin), and increased bone resorption marker (C-terminal type I collagen) levels. Conversely, individuals with PCOS and a BMI ≥27 kg/m2 exhibited increased vertebral and nonvertebral bone mineral density, with no significant changes in bone formation and resorption markers (except osteocalcin).

Conclusion

The findings of this study alert for a low bone mass, low bone formation, and increased bone resorption PCOS with a BMI <27 kg/m2.
Two distinct mechanisms of Plexin A function in Drosophila optic lobe lamination and morphogenesis
Authors: Bustillo Maria E. , Douthit Jessica , Astigarraga Sergio , Treisman Jessica E.
Published: May 2024

Visual circuit development is characterized by subdivision of neuropils into layers that house distinct sets of synaptic connections. We find that, in the Drosophila medulla, this layered organization depends on the axon guidance regulator Plexin A. In Plexin A null mutants, synaptic layers of the medulla neuropil and arborizations of individual neurons are wider and less distinct than in controls. Analysis of semaphorin function indicates that Semaphorin 1a, acting in a subset of medulla neurons, is the primary partner for Plexin A in medulla lamination. Removal of the cytoplasmic domain of endogenous Plexin A has little effect on the formation of medulla layers; however, both null and cytoplasmic domain deletion mutations of Plexin A result in an altered overall shape of the medulla neuropil. These data suggest that Plexin A acts as a receptor to mediate morphogenesis of the medulla neuropil, and as a ligand for Semaphorin 1a to subdivide it into layers. Its two independent functions illustrate how a few guidance molecules can organize complex brain structures by each playing multiple roles.
cellPLATO – an unsupervised method for identifying cell behaviour in heterogeneous cell trajectory data
Authors: Shannon Michael J. , Eisman Shira E. , Lowe Alan R. , Sloan Tyler F. W. , Mace Emily M.
Published: May 2024

Advances in imaging, segmentation and tracking have led to the routine generation of large and complex microscopy datasets. New tools are required to process this ‘phenomics’ type data. Here, we present ‘Cell PLasticity Analysis Tool’ (cellPLATO), a Python-based analysis software designed for measurement and classification of cell behaviours based on clustering features of cell morphology and motility. Used after segmentation and tracking, the tool extracts features from each cell per timepoint, using them to segregate cells into dimensionally reduced behavioural subtypes. Resultant cell tracks describe a ‘behavioural ID’ at each timepoint, and similarity analysis allows the grouping of behavioural sequences into discrete trajectories with assigned IDs. Here, we use cellPLATO to investigate the role of IL-15 in modulating human natural killer (NK) cell migration on ICAM-1 or VCAM-1. We find eight behavioural subsets of NK cells based on their shape and migration dynamics between single timepoints, and four trajectories based on sequences of these behaviours over time. Therefore, by using cellPLATO, we show that IL-15 increases plasticity between cell migration behaviours and that different integrin ligands induce different forms of NK cell migration.
Soft skeletons transmit force with variable gearing
Authors: Ellers Olaf , Ellers Kai-Isaak , Johnson Amy S. , Po Theodora , Heydari Sina , Kanso Eva , McHenry Matthew J.
Published: May 2024

A hydrostatic skeleton allows a soft body to transmit muscular force via internal pressure. A human's tongue, an octopus' arm and a nematode's body illustrate the pervasive presence of hydrostatic skeletons among animals, which has inspired the design of soft engineered actuators. However, there is a need for a theoretical basis for understanding how hydrostatic skeletons apply mechanical work. We therefore modeled the shape change and mechanics of natural and engineered hydrostatic skeletons to determine their mechanical advantage (MA) and displacement advantage (DA). These models apply to a variety of biological structures, but we explicitly consider the tube feet of a sea star and the body segments of an earthworm, and contrast them with a hydraulic press and a McKibben actuator. A helical winding of stiff, elastic fibers around these soft actuators plays a critical role in their mechanics by maintaining a cylindrical shape, distributing forces throughout the structure and storing elastic energy. In contrast to a single-joint lever system, soft hydrostats exhibit variable gearing with changes in MA generated by deformation in the skeleton. We found that this gearing is affected by the transmission efficiency of mechanical work (MA×DA) or, equivalently, the ratio of output to input work. The transmission efficiency changes with the capacity to store elastic energy within helically wrapped fibers or associated musculature. This modeling offers a conceptual basis for understanding the relationship between the morphology of hydrostatic skeletons and their mechanical performance.
Physical Activity, Fitness, and Body Composition After a 5-yr Exercise Counseling Intervention
Authors: Herb Neff Kirstie M. , Launius Kellsey N. , Schuh Leslie M. , Creel David B. , Inman Margaret M.
Published: May 2024

Introduction

Physical activity (PA) is recommended to optimize health after bariatric surgery. However, there is limited evidence on how to deliver these interventions and whether they are effective long-term. The present study aimed to examine PA levels, body composition, and physical fitness outcomes up to 5 yr after bariatric surgery following engagement in a PA intervention, with a focus on whether dose and/or timing of delivery impacts postoperative outcomes.

Methods

Individuals (n = 80) who completed a 6-month randomized treatment study to increase PA (phase 1) were invited to receive up to six exercise counseling sessions from 1 to 5 yr after operation (phase 2). Phase 2 participants (n = 64) completed assessments at 1, 1.5, 2, 3, 4, and 5 yr after operation.

Results

Five years after surgery, participants (84.4% female; mean age, 52.9 (standard deviation, 11.5); mean body mass index, 33.8 (standard error, 1.1)) increased minutes of moderate-to-vigorous physical activity (MVPA; P = 0.001) but not steps per day, exercise bouts per week, or bout minutes per week. Participants experienced significant cardiovascular endurance improvements but decreased strength (P < 0.05). Greater intervention dose (i.e., greater number of counseling visits attended 1–5 yr after surgery) was significantly associated with steps per day (P = 0.003), weight (P = 0.03), and nondominant handgrip strength (P = 0.002). Those who started counseling preoperatively (i.e., randomized to counseling in phase 1) versus 1 yr after surgery (i.e., beginning in phase 2) had greater steps per day (P = 0.04), exercise bouts per week (P = 0.006), and exercise bout minutes per week (P = 0.002). No other associations were significant.

Conclusions

Participants increased MVPA 5 yr after bariatric surgery and experienced improvements in cardiovascular functioning after engagement in a PA intervention. In general, individuals experienced modestly better outcomes with more treatment. Beginning exercise counseling preoperatively, instead of 1 yr postoperatively, improved PA but not body composition or physical fitness.
The concept of affect through the lens of intensity and becoming
Authors: Γούναρη Σωτηρία-Ισμήνη
Published: May 2024

Στην παρούσα διατριβή, μελετώ την έννοια του συναισθήματος-επίδρασης (affect) στις φιλοσοφίες των Baruch Spinoza και των Gilles Deleuze και Félix Guattari. Εκκινώντας από τη Σπινοζική αντίληψη του συναισθήματος ως τροποποίηση της εμμενούς υπόστασης, στη συνέχεια διερευνώ τις συνέπειες της σύλληψης του συναισθήματος ως διακύμανση της έντασης στο έργο των Deleuze και Guattari. Σύμφωνα με αυτούς, η ένταση, ή διαφορά καθαυτή, αποτελεί μέρος ενός τριαδικού μεταφυσικού σχήματος που περιλαμβάνει ακόμα το δυνητικό και το εν ενεργεία (ενεργό, actual). Αποτελεί μια δύναμη παραγωγής καινοτομίας την οποία επιτυγχάνει μέσω της διαζευκτικής σύνθεσης ετεροτήτων υπό το χαρακτηριστικό της τάσης προς ένα όριο. Η ένταση χαρακτηρίζει την κοινή στιγμή γένεσης της αισθητικότητας και της ιδεατότητας και αποτελεί όρο δυνατότητας και των δύο. Ακολούθως, το συναίσθημα δηλώνει τη διακύμανση αυτής της γενεσιουργού δύναμης του αισθητού και της ιδεατότητας και τη δημιουργική λειτουργία της αισθητικότητας. Χαρακτηριστικό το συναισθήματος είναι ότι προσδιορίζεται σε σχέση με ένα εντατικό οριακό σημείο μηδέν. Σε αυτό το οριακό σημείο συνυπάρχουν η φαινομενική ακύρωση της έντασης στην επανάληψη της συνήθειας, και η καινοτόμος δημιουργική δύναμη του χρόνου ή αλλιώς Θανάτου κατά Deleuze. Η ενότητα των εμπειρικών, εκτεταμένων οντοτήτων προϋποθέτει και εμπεριέχει τις προ-εμπειρικές μοναδικότητες (singularities) από τις οποίες προκύπτει. Το συναίσθημα νοείται έτσι ως μια πρωταρχική καινοτομία ή διαφορά που αποτελεί όρο δυνατότητας της εμφάνισης επαναλαμβανόμενων, συνηθισμένων τρόπων ύπαρξης. Στη συνέχεια αναλύεται η ηθική σημασία του συναισθήματος σε συμπλοκή με αυτό που οι Deleuze και Guattari ονομάζουν γίγνεσθαι-μειονότητα. Αυτή η συσχέτιση προκύπτει άμεσα από τη μεταφυσική της έντασης ως περάσματος στο γενετικό σημείο μηδέν το οποίο αποκαλύπτει τον δυναμισμό που προϋποτίθεται στα φαινομενικά ενοποιημένα αντικείμενα και από τον οποίον προκύπτουν τα τελευταία. Τέλος, αναλύεται η συνθετική λειτουργία του συναισθήματος ως συνδυασμού της διαφοράς καθ' εαυτής και της Χιουμιανής αρχής της εξωτερικότητας των σχέσεων. Ούτε εσωτερικό, ούτε εξωτερικό, το συναίσθημα αναδύεται στο ενδιάμεσο όριο δημιουργώντας νέες σχέσεις και τους αντίστοιχους όρους τους. Η συσχέτιση του συναισθήματος-επίδρασης με τα κοινώς εννοούμενα συναισθήματα (emotions) αξιολογείται σε σχέση με την απο-υποκειμενοποιητική τους λειτουργία, η οποία αναδεικνύεται στις καταφατικές λειτουργίες του πόνου και της από-προσωποποίησης. Περνώντας από την εμμενή του λειτουργία στον Σπινόζα στη μετα-ανθρώπινη λειτουργία του κατά Ντελέζ και Γκουαταρί, το συναίσθημα δηλώνει μια δημιουργική δύναμη παραγωγής του νέου.