bluuebunny/crossref_metadata_2025 huggingface dataset:
Astragaloside-IV promotes autophagy via the Akt/mTOR pathway to improve cellular lipid deposition
Authors: Liu Guo , Wang Ye-Hui , Zhang Ting , Li Ya-Qiong , Chen Xin-Yue , Dong Wei , Li Wei , Miao Qi-Xiang , Qiao Wen-Bo , Tian Hui-Qiang , Yin Shi-Long
Published: April 2024

The current study aimed to investigate the potential role of astragaloside IV (AS-IV) in improving cellular lipid deposition and its underlying mechanism. A fatty liver cell model was established by treating hepatoma cells with palmitic acid. AS-IV and SC79 were used for treatment. Oil Red O staining was applied to detect intracellular lipid deposition, and transmission electron microscopy was utilized to assess autophagosome formation. Immunofluorescence double staining was applied to determine microtubule-associated proteins 1A/1B light chain 3 (LC3) expression. Western blot analysis was performed to detect the expression of LC3, prostacyclin, Beclin-1, V-akt murine thymoma viral oncogene homolog (Akt), phosphorylated Akt, mTOR, and phosphorylated mTOR. Oil Red O staining revealed that AS-IV reduced intracellular lipid accumulation. Further, it increased autophagosome synthesis and the expression of autophagy proteins LC3 and Beclin-1 in the cells. It also reduced the phosphorylation levels of Akt and mTOR and the levels of prostacyclin. However, the effects of AS-IV decreased with SC79 treatment. In addition, LC3B + BODIPY493/503 fluorescence double staining showed that AS-IV reduced intracellular lipid deposition levels by enhancing autophagy. AS-IV can reduce lipid aggregation in fatty liver cells, which can be related to enhanced hepatocyte autophagy by inhibiting the Akt/mTOR signaling pathway.
Metacarpophalangeal joint reconstruction using a costal osteochondral graft: A case report
Authors: Ho Chien-Liang , Lee I-Ying , Hsu Hsiu-Yun , Kuo Li-Chieh , Fang Jing-Jing
Published: April 2024

Rationale:

The conventional treatment of giant cell tumors is intralesional curettage with local adjuvant therapy. Because hand tumors have a high local recurrence, the primary goal for treating tumors of the hand is to eradicate the lesion.

Patient concerns:

To preserve the metacarpophalangeal (MCP) joint function as well as avoid further recurrence after surgery.

Diagnoses:

The giant cell tumor invades the patient’s MCP joint in an index proximal phalanx.

Interventions:

Using computer-aided design and three-dimensional printing techniques, we reformed the original shapes of the MCP joint and its peripheral bone to replica models. The surgeon then performed an en bloc resection and proximal phalanx with MCP joint reconstruction by fabricating the patient’s costal osteochondral graft during the operation.

Outcomes:

After 6 months of rehabilitation, the patient’s finger functions could pinch and grasp objects naturally. At the 1-year follow-up, the range of motion of the MCP, proximal interphalangeal, and distal interphalangeal joints improved from flexion of 35° to 60°, 75° to 85°, and 60° to 80°, respectively. The hand function achieved the mean performance of non-preferred hands for young females at the postoperative 3-year follow-up.

Lessons:

The customized prototyping technique has the potential to replica the original patient’s bony graft to reach the goal of minimizing the defects at the donor site and maximizing the function of the reconstructed MCP joint.
Predicting the risk of lung cancer using machine learning: A large study based on UK Biobank
Authors: Zhang Siqi , Yang Liangwei , Xu Weiwen , Wang Yue , Han Liyuan , Zhao Guofang , Cai Ting
Published: April 2024

In response to the high incidence and poor prognosis of lung cancer, this study tends to develop a generalizable lung-cancer prediction model by using machine learning to define high-risk groups and realize the early identification and prevention of lung cancer. We included 467,888 participants from UK Biobank, using lung cancer incidence as an outcome variable, including 49 previously known high-risk factors and less studied or unstudied predictors. We developed multivariate prediction models using multiple machine learning models, namely logistic regression, naïve Bayes, random forest, and extreme gradient boosting models. The performance of the models was evaluated by calculating the areas under their receiver operating characteristic curves, Brier loss, log loss, precision, recall, and F1 scores. The Shapley additive explanations interpreter was used to visualize the models. Three were ultimately 4299 cases of lung cancer that were diagnosed in our sample. The model containing all the predictors had good predictive power, and the extreme gradient boosting model had the best performance with an area under curve of 0.998. New important predictive factors for lung cancer were also identified, namely hip circumference, waist circumference, number of cigarettes previously smoked daily, neuroticism score, age, and forced expiratory volume in 1 second. The predictive model established by incorporating novel predictive factors can be of value in the early identification of lung cancer. It may be helpful in stratifying individuals and selecting those at higher risk for inclusion in screening programs.
Leukocyte counts and ratios as potential predictors of large vessel occlusion in acute ischemic stroke: A retrospective cohort study
Authors: Wang Yu , Zhang Jie , Dai Lin , Kong Yongmei , Wei Yuqing , Wu Lijuan , Yin Juntao
Published: April 2024

Leukocyte counts and ratios are independent biomarkers to determine the severity and prognosis of acute ischemic stroke (AIS). In AIS, the connection between leukocytes and large vessel occlusion (LVO) is uncertain. This study aims to determine the relationship between the existence of LVO and leukocyte counts and ratios on admission to AIS. Patients were retrospectively evaluated within six hours of AIS starting between January 2019 and April 2023. On admission, blood specimens were collected, and leukocyte subtype counts were promptly analyzed. Computed tomography or digital subtraction angiography were utilized to verify the existence of LVO. Regression analysis and receiver operating characteristic (ROC) curves were employed to investigate the connections between the counts and ratios of leukocytes and the existence of LVO, as well as the discriminatory ability of these variables in predicting LVO. Total white blood cell (WBC) count, neutrophil count, and neutrophil-to-lymphocyte ratio (NLR) were substantially higher in the LVO existence group compared to the LVO absence group, whereas the ratio of eosinophils to neutrophils (ENR × 102) was lower (P < .001, respectively). Significant associations were observed between total WBC counts, neutrophil counts, NLR, and ENR × 102 and the existence of LVO (P < .001, respectively). Total WBC counts, neutrophil counts, NLR, and ENR × 102 had respective areas under the curves (AUC) of 0.730, 0.748, 0.704, and 0.680 for identifying LVO. Our results show that in AIS patients, the existence of LVO is independently associated with elevated total WBC and neutrophil counts, high NLR, and low ENR × 102 levels. Neutrophil and total WBC counts, as well as NLR and levels of ENR × 102, may serve as potential biomarkers for predicting LVO. Neuroinflammation, based on the existence of LVO, should be given particular attention in future investigations.
The impact of creatine kinase and base excess on the clinical outcome of crush injuries sustained during the Kahramanmaras/Turkey earthquakes on February 6, 2023
Authors: Gur Aysenur , Simsek Yeliz
Published: April 2024

The aim of the study is to determine the usefulness of base excess (BE) and creatine kinase (CK) in predicting the extent of damage to the extremities, the need for hemodialysis, and the likelihood of mortality in crush injuries. Our study included patients who were affected by the earthquakes that occurred in Kahramanmaras/Turkey on February 6, 2023 and were diagnosed with crush injuries. The study was a retrospective observational study. We used chi-square test, independent sample t test, analysis of variance (ANOVA) to examine whether CK and BE values can be used to predict damage to the extremities, hemodialysis requirement, and mortality. A total of 299 patients were included in the study. A statistically significant relationship was found between BE and extremity damage, hemodialysis requirement, and mortality (P < .005). A statistically significant difference was also seen in terms of extremity damage and hemodialysis requirement with CK (P < .001), while there was no statistically significant difference seen in mortality (P = .204). BE may serve as a predictive biomarker for the development of extremities damage, hemodialysis requirement, and mortality. CK is not predictive of mortality.
Lysine and salt-sensitive hypertension
Authors: Dissanayake Lashodya V. , Palygin Oleg , Staruschenko Alexander
Published: April 2024

Purpose of review

Salt-sensitive (SS) hypertension and its associated kidney damage have been extensively studied, yet proper therapeutic strategies are lacking. The interest in altering the metabolome to affect renal and cardiovascular disease has been emerging. Here, we discuss the effect and potential mechanism behind the protective effect of lysine, an essential amino acid, on the progression of SS hypertension.

Recent findings

We have recently demonstrated that administering lysine in an SS rodent model can control the progression of hypertension. Both the animal and pilot human studies showed that lysine can efficiently inhibit tubular reabsorption of albumin and protect the kidneys from further damage. In addition, we conducted multilevel omics studies that showed increased lysine conjugation and excretion, leading to the depletion of harmful metabolites and an increase in useful ones.

Lysine's twofold action involves both mechanically flushing protein from proximal tubules to shield the kidneys and initiating metabolic adaptations in the kidneys. This results in a net positive impact on SS hypertension. While further research is necessary to apply the current findings in clinical settings, this study offers some evidence suggesting that lysine supplementation holds promise as a therapeutic approach for hypertensive kidney disease.
APOE and familial hypercholesterolemia
Authors: Civeira Fernando , Martín César , Cenarro Ana
Published: April 2024

Purpose of review

Autosomal dominant hypercholesterolemia is a common cause of cardiovascular disease. In addition to the classic genes that cause hypercholesterolemia, LDLR, APOB and PCSK9, a new locus has emerged as a candidate to be the cause of this hyperlipidemia, the p.(Leu167del) mutation in the APOE gene.

Recent findings

Various studies have demonstrated the involvement of the p.(Leu167del) mutation in the APOE gene in hypercholesterolemia: Studies of family segregation, lipoprotein composition by ultracentrifugation and proteomic techniques, and functional studies of VLDL-carrying p.(Leu167del) internalization with cell cultures have demonstrated the role of this mutation in the cause of hypercholesterolemia. The phenotype of individuals carrying the p.(Leu167del) in APOE is indistinguishable from familial hypercholesterolemia individuals with mutations in the classic genes. However, a better response to lipid-lowering treatment has been demonstrated in these APOE mutation carrier individuals.

Therefore, APOE gene should be considered a candidate locus along with LDLR, APOB, and PCSK9 to be investigated in the genetic diagnosis of familial hypercholesterolemia.
Familial hypercholesterolemia-Plus: is the metabolic syndrome changing the clinical picture of familial hypercholesterolemia?
Authors: Brunham Liam R.
Published: April 2024

Purpose of review

The purpose of this review article was to describe recent advances in our knowledge about how diabetes and metabolic syndrome are changing the face of familial hypercholesterolemia.

Recent findings

Heterozygous familial hypercholesterolemia, most commonly caused by disruption to LDL receptor function, leads to lifelong elevation of LDL cholesterol and increased risk of atherosclerotic cardiovascular disease. Familial hypercholesterolemia was originally described as a form of ‘pure’ hypercholesterolemia, in the sense that levels of LDL were uniquely affected. Studies of familial hypercholesterolemia among individuals of predominantly Western European descent conformed to the perception that individuals with familial hypercholesterolemia tended to be lean and otherwise metabolically healthy. More recently, as we have studied familial hypercholesterolemia in more diverse global populations, we have learned that in some regions, rates of diabetes and obesity among familial hypercholesterolemia patients are very high, mirroring the global increases in the prevalence of metabolic disease.

When diabetes and metabolic disease coexist, they amplify the cardiovascular risk in familial hypercholesterolemia, and may require more aggressive treatment.
High-Flow Nasal Cannula Versus Nasal Prong Bubble Continuous Positive Airway Pressure in Children With Moderate to Severe Acute Bronchiolitis: A Randomized Controlled Trial*
Authors: Maya Malini , Rameshkumar Ramachandran , Selvan Tamil , Delhikumar Chinnaiah Govindhareddy
Published: April 2024

OBJECTIVES:

To compare high-flow nasal cannula (HFNC) versus nasal prong bubble continuous positive airway pressure (b-CPAP) in children with moderate to severe acute bronchiolitis.

DESIGN:

A randomized controlled trial was carried out from August 2019 to February 2022. (Clinical Trials Registry of India number CTRI/2019/07/020402).

SETTING:

Pediatric emergency ward and ICU within a tertiary care center in India.

PATIENTS:

Children 1–23 months old with moderate to severe acute bronchiolitis.

INTERVENTION:

Comparison of HFNC with b-CPAP, using a primary outcome of treatment failure within 24 hours of randomization, as defined by any of: 1) a 1-point increase in modified Wood’s clinical asthma score (m-WCAS) above baseline, 2) a rise in respiratory rate (RR) greater than 10 per minute from baseline, and 3) escalation in respiratory support. The secondary outcomes were success rate after crossover, if any, need for mechanical ventilation (invasive/noninvasive), local skin lesions, length of hospital stay, and complications.

RESULTS:

In 118 children analyzed by intention-to-treat, HFNC (n = 59) versus b-CPAP (n = 59) was associated with a lower failure rate (23.7% vs. 42.4%; relative risk [95% CI], RR 0.56 [95% CI, 0.32–0.97], p = 0.031). The Cox proportion model confirmed a lower hazard of treatment failure in the HFNC group (adjusted hazard ratio 0.48 [95% CI, 0.25–0.94], p = 0.032). No crossover was noted. A lower proportion escalated to noninvasive ventilation in the HFNC group (15.3%) versus the b-CPAP group (15.3% vs. 39% [RR 0.39 (95% CI, 0.20–0.77)], p = 0.004). The HFNC group had a longer median (interquartile range) duration of oxygen therapy (4 [3–6] vs. 3 [3–5] d; p = 0.012) and hospital stay (6 [5–8.5] vs. 5 [4–7] d, p = 0.021). No significant difference was noted in other secondary outcomes.

CONCLUSION:

In children aged one to 23 months with moderate to severe acute bronchiolitis, the use of HFNC therapy as opposed to b-CPAP for early respiratory support is associated with a lower failure rate and, secondarily, a lower risk of escalation to mechanical ventilation.
Heterogeneous Uptake of 68Ga-DOTATATE and 18F-FDG in Initial Diagnosed Neuroendocrine Tumors Patients
Authors: Zhou Yi , Li Li , Wang Hui , Huang He-xiao , Cao Dan , Ke Neng-wen , Su Ming-gang , Tian Rong
Published: April 2024

Purpose

This study was designed to assess the uptake heterogeneity in neuroendocrine tumor (NET) patients at initial diagnosis with dual-tracer PET imaging and the staging changes and prognostic value it brings to explore the indication of the use of dual-tracer PET.

Methods

Fifty-one newly diagnosed patients with pathologically confirmed NET who underwent 18F-FDG and 68Ga-DOTATATE PET imaging between January 2020 and September 2022 were enrolled. Dual-tracer uptake patterns were classified into 3 groups: A. 68Ga-DOTATATE positive and 18F-FDG negative, B. 68Ga-DOTATATE positive and 18F-FDG positive, and C. 68Ga-DOTATATE negative and 18F-FDG positive. Descriptive statistics were used to evaluate the heterogeneity of dual-tracer uptake patterns among different grading (G) groups, between primary and metastatic lesions, and staging changes. Moreover, dual-tracer uptake patterns, grade, age, sex, and stage were compared with progression-free survival (PFS) by Cox regression.

Results

In the different G groups, none of the patients with dual-tracer uptake pattern A had grade 3 histology, but 57% of patients with grade 1 disease had FDG avidity (25% of them resulting in dual-tracer uptake pattern C). Patients with no metastasis were well differentiated, but one of them presented with dual-tracer uptake pattern C. Different uptake patterns were also observed between primary and metastatic lesions, particularly 44% of patients with dual-tracer uptake pattern A of primary with FDG avidity of metastases. Moreover, 9 (17.6%) had new lesions detected by additional 18F-FDG PET imaging, and 3 of them (5.9%) had clinical stage changed accordingly. The Cox regression test showed that the dual-tracer uptake patterns were significantly correlated with PFS by univariate and multivariate analyses (P = 0.026 and 0.039, respectively), whereas the grade and stage did not correlate with survival (all P>0.05).

Conclusion

The current study has proven the uptake heterogeneity of the NET at initial diagnosis and demonstrated the staging and prognostic value of dual-tracer PET imaging. Our preliminary results have confirmed the importance of dual-tracer imaging modalities and concluded that dual-tracer PET imaging could be considered as prognostic tool for all patients with an initial diagnosis of NET.
Implementing Strategy-Based Instruction for Struggling Writers via Telepractice
Authors: Koutsoftas Anthony D. , Hoover Karen
Published: April 2024

In this clinical tutorial, we describe the implementation of interventions provided to struggling writers using telepractice as the method of service delivery. The intervention of focus in this article was provided by graduate students who received advanced training in supporting writing to elementary school children with and without learning disabilities. The protocols developed for this study were framed by a theoretical framework for writing (K. D. Ritchey et al., 2016) and based on current best evidence for supporting struggling writers (e.g., A. L. Poch et al., 2022; S. Graham & D. Perin, 2007). In short, we lifted from the research literature available best practices for writing interventions and adapted these for telepractice with elementary-age schoolchildren identified as struggling writers. As part of this clinical tutorial, four different case studies are provided that illustrate how the intervention was adapted to meet individual student needs. Clinical implications for adapting interventions delivered via telepractice for struggling writers are provided alongside future research directions.
How suitable is freshwater sponge Ephydatia fluviatilis (Linnaeus, 1759) for time-integrated biomonitoring of microbial water quality?
Authors: Cartwright Allison , Dooley James S. G. , McGonigle Chris D. , Arnscheidt Joerg
Published: April 2024

Faecal pollution of water by bacteria has a negative effect on water quality and can pose a potential health hazard. Conventional surveillance of microbial water quality relies on the analysis of low-frequency spot samples and is thus likely to miss episodic or periodic pollution. This study aimed to investigate the potential of filter-feeding sponges for time-integrated biomonitoring of microbial water quality. Laboratory trials tested the effects of different ratios of bacterial abundance and the sequence of exposure on bacterial retention by the freshwater sponge Ephydatia fluviatilis (Linnaeus, 1759) to establish its potential to indicate bacterial exposure. Gemmule grown sponges were simultaneously exposed to Escherichia coli and Enterococcus faecalis but at different ratios (Trial 1) or individually exposed to each bacterial species but in different sequential order (Trial 2). The E. coli and E. faecalis retained in each sponge was quantified by culture on selective agars. Data analysis was conducted using the Kruskal–Wallis test and/or the Mann–Whitney U test to compare between the numbers of bacteria retained in each treatment. Additionally, the Wilcoxon matched-paired signed-rank test was used for comparison of the different bacterial abundances retained within each individual sponge. Sponges from all trials retained E. coli and E. faecalis in small numbers relative to the exposure (<0.05 % Trial 1 and <0.07 % Trial 2) but exhibited higher retention of E. coli. Higher abundance of either bacterial species resulted in significantly lower (P<0.005) retention of the same species within sponges (Trial 1). An initial exposure to E. coli resulted in significantly higher (P=0.040) retention of both bacterial species than when sponges were exposed to E. faecalis first (Trial 2).Bacterial retention by sponges was neither quantitatively representative of bacterial abundance in the ambient water nor the sequence of exposure. This implies either selective filtration or an attempt by sponges to prevent infection. However, freshwater sponges may still be useful in biomonitoring as qualitative time-integrated samplers of faecal indicator bacteria as they detect different bacteria present in the water even if their quantities cannot be estimated.
Glucose-loaded dopamine transporter is associated with mood altering effect of sweet foods and control over eating sweets
Authors: Pak Kyoungjune , Kim Jihyun , Kim Keunyoung , Seo Seongho , Lee Myung Jun
Published: April 2024

Dopamine transporter (DAT) mediates reuptake of extracellular dopamine into presynaptic neurons. We investigated the effects of glucose loading on striatal DAT in healthy young adults who underwent18F-FP-CIT positron emission tomography (PET) scans, and sweet taste questionnaire (STQ). Thirty-five healthy subjects were enrolled in this study. Each subject visited the institution three times, for three brain PET scans (two18F-FP-CIT PET scans after the infusion of glucose or placebo and one18F-Fluorodeoxyglucose PET scan). All subjects underwent STQ, 12-item self-reporting to evaluate subjects’ reactions to eating sweets, craving for sweets and degree of control over eating sweet foods (STQ 1: sensitivity to mood altering effect of sweets, and STQ 2: impaired control over eating sweet foods). We created Bayesian models separately with STQ 1, and STQ 2 as predictors, with DAT availability and brain glucose uptake as a dependent variable. From caudate, glucose-loaded DAT availability was significantly higher than placebo-loaded DAT availability, and from putamen, glucose-loaded DAT availability showed the higher trend than placebo-loaded DAT availability. STQ was positively associated with glucose-loaded DAT availability. The effect of STQ markedly overlapped with zero on placebo-loaded DAT availability, and brain glucose uptake. In conclusion, the change of striatal DAT availability after glucose loading is associated with the vulnerability to sweet foods. This may indicate that individuals with higher DAT availability after glucose loading experience a rapid clearance of synaptic dopamine after consuming sweet foods, potentially leading to a desire for additional sweet foods.
Magnetomyography: A novel modality for non-invasive muscle sensing
Authors: Yun Richy , Gonzalez Gabriel , Gerrard Isabel , Csaky Richard , Dash Debadatta , Kittle Evan , Deka Nishita , Labanowski Dominic
Published: April 2024

The measurement of magnetic fields generated by skeletal muscle activity, called magnetomyography (MMG), has seen renewed interest from the academic community in recent years. Although studies have demonstrated complex models of MMG and experiments classifying between different movements using MMG, there has yet to be time frequency analysis of MMG as well as concurrent recordings of MMG and its electrical counterpart, surface electromyography (sEMG). Here, we aim to better understand MMG in the context of sEMG by simultaneously recording both modalities during various muscle contraction tasks. We found that, similar to sEMG, MMG shows highly linearly correlated power to the degree of muscle contraction, has a unimodal distribution in spectral power, and can detect changes in muscle fatigue via changes in the spectral distribution. One main difference we found was that MMG typically has more high frequency content compared to sEMG, even when accounting for the filtering induced by the size of the sEMG electrodes. We additionally demonstrate empirically the decrease in MMG power due to distance from the arm and show MMG decreases slower than the inverse square law and can be measured up to 50 mm from the surface of the skin. Finally, we were able to capture MMG with non-OPM sensors showing that sensor technology has made great strides towards enabling MMG applications.
Pharmacological inhibition of astrocytic transglutaminase 2 facilitates the expression of a neurosupportive astrocyte reactive phenotype in association with increased histone acetylation
Authors: Delgado Thomas , Emerson Jacen , Hong Matthew , Keillor Jeffrey W. , Johnson Gail VW
Published: April 2024

Astrocytes play critical roles in supporting structural and metabolic homeostasis in the central nervous system (CNS). CNS injury leads to the development of a range of reactive phenotypes in astrocytes whose molecular determinants are poorly understood. Finding ways to modulate astrocytic injury responses and leverage a pro-recovery phenotype holds promise in treating CNS injury. Recently, it has been demonstrated that ablation of astrocytic transglutaminase 2 (TG2) modulates the phenotype of reactive astrocytes in a way that improves neuronal injury outcomes bothin vitroandin vivo. In anin vivomouse model, pharmacological inhibition of TG2 with the irreversible inhibitor VA4 phenocopies the neurosupportive effects of TG2 deletion in astrocytes. In this study, we provide insights into the mechanisms by which TG2 deletion or inhibition result in a more neurosupportive astrocytic phenotype. Using a neuron-astrocyte co-culture model, we show that VA4 treatment improves the ability of astrocytes to support neurite outgrowth on an injury-relevant matrix. To better understand how pharmacologically altering TG2 affects its ability to regulate reactive astrocyte phenotypes, we assessed how VA4 inhibition impacts TG2’s interaction with Zbtb7a, a transcription factor we have previously identified as a functionally relevant TG2 nuclear interactor. The results of these studies demonstrate that VA4 significantly decreases the interaction of TG2 and Zbtb7a. TG2’s interactions with Zbtb7a, as well as a wide range of other transcription factors and chromatin regulatory proteins, suggest that TG2 may act as an epigenetic regulator to modulate gene expression. To begin to understand if TG2-mediated epigenetic modification may impact astrocytic phenotypes in our models, we interrogated the effect of TG2 deletion and VA4 treatment on histone acetylation and found significantly greater acetylation in both experimental groups. Consistent with these findings, previous RNA-sequencing and our present proteomic analysis also supported a predominant transcriptionally suppressive role of TG2 in astrocytes. Our proteomic data additionally unveiled pronounced changes in lipid and antioxidant metabolism in astrocytes with TG2 deletion or inhibition, which likely contribute to the enhanced neurosupportive function of these astrocytes.
Endothelial and neuronal engagement by AAV-BR1 alleviates neurological symptoms and cholesterol deposition in a mouse model of Niemann-Pick type C2
Authors: Rasmussen Charlotte Laurfelt Munch , Heegaard Christian Würtz , Thomsen Maj Schneider , Hede Eva , Laczek Bartosz , Körbelin Jakob , Thomsen Louiza Bohn , Schwaninger Markus , Moos Torben , Burkhart Annette
Published: April 2024

Background

Patients with the genetic disorder Niemann-Pick type C2 disease (NP-C2) suffer from lysosomal accumulation of cholesterol causing both systemic and severe neurological symptoms. In a murine NP-C2 model, otherwise successful intravenous Niemann-Pick C2 protein (NPC2) replacement therapy fails to alleviate progressive neurodegeneration as infused NPC2 is unable to cross the blood-brain barrier (BBB). Genetic modification of brain endothelial cells (BECs) is thought to enable secretion of recombinant proteins thereby overcoming the restrictions of the BBB. We hypothesized that BBB-directed gene therapy using the AAV-BR1-NPC2 vector would transduce both BECs and neurons in a mouse model of NP-C2 (Npc2-/-).

Methods

Six weeks oldNpc2-/- mice were intravenously injected with the AAV-BR1-NPC2 vector. Post-mortem analyses included gene expression analyses, determination of NPC2 transduction in the CNS, and co-detection of cholesterol with NPC2 in neurons.

Results

The vector exerted tropism for BECs and neurons resulting in a widespread NPC2 distribution in the brain with a concomitant reduction of cholesterol in adjacent neurons, presumably not transduced by the vector.

Conclusion

The data suggests cross-correcting gene therapy to the brain via delivery of NPC2 from BECs and neurons.
The disappointment centre of the brain gets exciting: A systematic review of habenula dysfunction in depression
Authors: Cameron Sarah , Weston-Green Katrina , Newell Kelly A
Published: April 2024

Background

The habenula is an epithalamic brain structure that acts as a neuroanatomical hub connecting the limbic forebrain to the major monoamine centres. Abnormal habenula activity is increasingly implicated in depression, with a surge in publications on this topic in the last 5 years. Direct stimulation of the habenula is sufficient to induce a depressive phenotype in rodents, suggesting a causative role in depression. However, the molecular basis of habenula dysfunction in depression remains elusive and it is unclear how the preclinical advancements translate to the clinical field.

Methods

A systematic literature search was conducted following the PRISMA guidelines. The two search terms depress* and habenula* were applied across the databases Scopus, Web of Science and PubMed. Studies eligible for inclusion must have examined changes in the habenula in clinical cases of depression or preclinical models of depression.

Results

Preclinical studies (n=57) measured markers of habenula activity (n=16) and neuronal firing (n=21), largely implicating habenula hyperactivity in depression. Neurotransmission was briefly explored (n=13), suggesting imbalances within excitatory and inhibitory habenula signalling. Additional preclinical studies reported neuroconnectivity (n=1), inflammatory (n=2), genomic (n=2) and circadian rhythm (n=2) abnormalities. Seven preclinical studies (12.2%) included both males and females. From these, 5 studies (71%) reported a significant difference between the sexes in at least one habenula measure taken. Clinical studies (n=18) reported abnormalities in habenula connectivity (n=11), volume (n=5) and molecular markers (n=2). Clinical studies generally included male and female subjects (n=15), however, few of these studies examined sex as a biological variable (n=5)

Conclusions

Both preclinical and clinical evidence suggest the habenula is disrupted in depression. However, there are opportunities for sex-specific analyses across both areas. Preclinical evidence consistently suggests habenula hyperactivity as a primary driver for the development of depressive symptoms. Clinical studies support gross habenula abnormalities such as altered activation, connectivity, and volume, with emerging evidence of blood brain barrier dysfunction, however, progress is limited by a lack of detailed molecular analyses.
Short report: A judgment bias task reveals stress produces a negative affective state in cuttlefish
Authors: Giancola-Detmering Sarah E. , Crook Robyn J.
Published: April 2024

Judgment Bias Tasks (JBT) are used to assess emotional state and welfare of animals in zoos, farms, and laboratories, based on a subject’s interpretation of an ambiguous or intermediate cue. Animals in positive affective states are more likely to interpret the ambiguous cue positively, reflecting optimistic bias and animals with negative affect are more likely to interpret ambiguous cues pessimistically. Here, we developed a JBT assay for the stumpy-spined cuttlefish,Sepia bandensis, to determine whether cuttlefish exhibit negative affective states resulting from chronic and acute stress. Cuttlefish learned to associate food with a visual cue. Positive and neutral cues were presented twice daily until animals oriented to the positive cue and searched for food. After training, one treatment group was exposed to combined chronic and acute stress produced by 5 days of impoverished housing and once-daily simulated net capture. Our control group received no stress experience. In test trials performed after the stress experience, stressed animals had higher latencies to approach ambiguous cues, spent significantly less time in rooms with ambiguous cues once they entered, and were less likely to enter first into the ambiguous cue-paired room compared with controls. These behaviors suggest that stress induces pessimistic judgment bias in cuttlefish, the first indication of this capacity in cephalopods.
Protein Translation Dysregulation and Immune Cell Evasion Define Metastatic Clones in HPV-related Cancer of the Oropharynx
Authors: Chin Venessa T , Muskovic Walter , McCloy Rachael A , Neavin Drew R , Alquicira-Hernandez Jose , Arora Himanshi , Senabouth Anne , Keith Patricia , Spenceley Ellie , Murphy Angela , Kaczorowski Dominik , Floros Peter , Earls Peter , Leavers Brett , Crawford Julia , Gallagher Richard , Powell Joseph E.
Published: April 2024

Head and neck cancers, representing the seventh most common malignancy globally, have seen a shift in causative factors from traditional smoking and alcohol use to human papillomavirus (HPV) infection, now accounting for up to 80% of oropharyngeal cancers. We identify the cellular and clonal mechanisms underlying immune avoidance and metastasis by analysing single-cell and spatial genomic data from primary and metastatic cancers. We first map the clonal evolution of malignant cells based on the accumulation of mutations. We identify metastasising clones based on mutational similarity scores between cells in the primary and lymph node metastasis. Genomic analysis of metastasising and non-metastasising clones identified virally mediated protein translation relief (P=4.24x10-24) pathway underlying metastatic expansion. We show that in metastatic clones, this process is driven through upregulation of transition-initiating factors,EIF4E(P=1.5x10-13) andEIFG1(P<2.22x10-16), and suppression of regulatory kinasesEIF4EBP1(P=2.1x10),EIF2AK2(P<2.22x10-16), andEIF2S1(P<2.22x10-16). We subsequently identify that metastatic clones have a corresponding downregulation of theJAK/STATpathway and immunoproteasome genesPSMB8(P<2.22x10-16) andPSMB9(P<2.22x10-16), suggesting these clones escape immune surveillance through decreasedINFinflammatory response and antigen presentation. We validate these results using spatial RNA-seq data, where metastatic cancer clones show decreased cell-to-cell interactions with CD4 T-effector memory cells (CD4TEM) (P=0.0077), CD8 T-exhausted cells (CD8Ex) (P=0.0191), and innate lymphoid cells (ILC) (P=0.04). Finally, we demonstrate that the upregulation of cap-independent translational drives cell proliferation in metastatic clones through the expression of translation initiation factors (EIF4G1: P<2.22x10-16). Our results provide evidence of the mechanisms by which virally induced cancer clones lead to advanced disease and poor prognosis in patients.
Augmenting mortality prediction with medication data and machine learning models
Authors: Murray Brian , Zhang Tianyi , Most Amoreena , Chen Xianyan , Smith Susan E. , Devlin John W. , Murphy David J. , Sikora Andrea , Kamaleswaran Rishikesan
Published: April 2024

Background

In critically ill patients, complex relationships exist among patient disease factors, medication management, and mortality. Considering the potential for nonlinear relationships and the high dimensionality of medication data, machine learning and advanced regression methods may offer advantages over traditional regression techniques. The purpose of this study was to evaluate the role of different modeling approaches incorporating medication data for mortality prediction.

Methods

This was a single-center, observational cohort study of critically ill adults. A random sample of 991 adults admitted ≥ 24 hours to the intensive care unit (ICU) from 10/2015 to 10/2020 were included. Models to predict hospital mortality at discharge were created. Models were externally validated against a temporally separate dataset of 4,878 patients. Potential mortality predictor variables (n=27, together with 14 indicators for missingness) were collected at baseline (age, sex, service, diagnosis) and 24 hours (illness severity, supportive care use, fluid balance, laboratory values, MRC-ICU score, and vasopressor use) and included in all models. The optimal traditional (equipped with linear predictors) logistic regression model and optimal advanced (equipped with nature splines, smoothing splines, and local linearity) logistic regression models were created using stepwise selection by Bayesian information criterion (BIC). Supervised, classification-based ML models [e.g., Random Forest, Support Vector Machine (SVM), and XGBoost] were developed. Area under the receiver operating characteristic (AUROC), positive predictive value (PPV), and negative predictive value (NPV) were compared among different mortality prediction models.

Results

A model including MRC-ICU in addition to SOFA and APACHE II demonstrated an AUROC of 0.83 for hospital mortality prediction, compared to AUROCs of 0.72 and 0.81 for APACHE II and SOFA alone. Machine learning models based on Random Forest, SVM, and XGBoost demonstrated AUROCs of 0.83, 0.85, and 0.82, respectively. Accuracy of traditional regression models was similar to that of machine learning models. MRC-ICU demonstrated a moderate level of feature importance in both XGBoost and Random Forest. Across all ten models, performance was lower on the validation set.

Conclusions

While medication data were not included as a significant predictor in regression models, addition of MRC-ICU to severity of illness scores (APACHE II and SOFA) improved AUROC for mortality prediction. Machine learning methods did not improve model performance relative to traditional regression methods.
Crisis Readiness and Innovation for Burnout Prevention Among Community Health Workers
Authors: Raghavan Ramya
Published: April 2024

The performance of community health workers is an important factor in the success of health systems in underserved, vulnerable populations. Community health workers (CHWs) face work-related burnout. This study used a survey instrument to identify facilitators and barriers to a health crisis or pandemic preparedness. Causes of burnout and factors of crisis readiness were examined, including CHWs’ health status, readiness to use technology, and organisational culture. Findings suggest that more technology training and organisational support are needed to develop a resilient healthcare system. Increased workloads and demanding work schedules contribute to burnout, highlighting the need for support resources to promote the physical and mental health of CHWs. The study also collected data on CHWs’ perspectives on organisational commitment and individual innovation behaviours. The sample population is motivated to try new ideas and work methods to meet dynamic challenges and work expectations. Despite systemic shortcomings, more than 50% of them can envision a career with their community health organisation. Therefore, collaborative efforts are needed to create a work environment that promotes the physical well-being and professional development of CHWs. It is of practical importance for managers to value fostering innovation and organisational commitment in their healthcare workforce. In addition, our study is relevant to policymakers at local and central levels to plan national programmes for crisis preparedness and building a healthy nation.
Genomic and phenotypic correlates of mosaic loss of chromosome Y in blood
Authors: Jakubek Yasminka A. , Ma Xiaolong , Stilp Adrienne M. , Yu Fulong , Bacon Jason , Wong Justin W. , Aguet Francois , Ardlie Kristin , Arnett Donna , Barnes Kathleen , Bis Joshua C. , Blackwell Tom , Becker Lewis C. , Boerwinkle Eric , Bowler Russell P. , Budoff Matthew J. , Carson April P. , Chen Jiawen , Cho Michael H. , Coresh Josef , Cox Nancy , de Vries Paul S. , DeMeo Dawn L. , Fardo David W. , Fornage Myriam , Guo Xiuqing , Hall Michael E. , Heard-Costa Nancy , Hidalgo Bertha , Irvin Marguerite Ryan , Johnson Andrew D. , Kenny Eimear E. , Levy Dan , Li Yun , Lima Joao AC. , Liu Yongmei , Loos Ruth J.F. , Machiela Mitchell J. , Mathias Rasika A. , Mitchell Braxton D. , Murabito Joanne , Mychaleckyj Josyf C. , North Kari , Orchard Peter , Parker Stephen CJ. , Pershad Yash , Peyser Patricia A. , Pratte Katherine A. , Psaty Bruce M. , Raffield Laura M. , Redline Susan , Rich Stephen S. , Rotter Jerome I. , Shah Sanjiv J. , Smith Jennifer A. , Smith Aaron P. , Smith Albert , Taub Margaret , Tiwari Hemant K. , Tracy Russell , Tuftin Bjoernar , Bick Alexander G. , Sankaran Vijay G. , Reiner Alexander P. , Scheet Paul , Auer Paul L.
Published: April 2024

Mosaic loss of Y (mLOY) is the most common somatic chromosomal alteration detected in human blood. The presence of mLOY is associated with altered blood cell counts and increased risk of Alzheimer’s disease, solid tumors, and other age-related diseases. We sought to gain a better understanding of genetic drivers and associated phenotypes of mLOY through analyses of whole genome sequencing of a large set of genetically diverse males from the Trans-Omics for Precision Medicine (TOPMed) program. This approach enabled us to identify differences in mLOY frequencies across populations defined by genetic similarity, revealing a higher frequency of mLOY in the European American (EA) ancestry group compared to those of Hispanic American (HA), African American (AA), and East Asian (EAS) ancestry. Further, we identified two genes (CFHR1andLRP6) that harbor multiple rare, putatively deleterious variants associated with mLOY susceptibility, show that subsets of human hematopoietic stem cells are enriched for activity of mLOY susceptibility variants, and that certain alleles on chromosome Y are more likely to be lost than others.
Effects of parental autoimmune diseases on type 1 diabetes in offspring can be partially explained by HLA and non-HLA polymorphisms
Authors: Wang Feiyi , Liu Aoxing , Yang Zhiyu , Vartiainen Pekka , Jukarainen Sakari , Koskela Satu , Oram Richard A. , Allen Lowri , Ritari Jarmo , Partanen Jukka , FinnGen Markus Perola , Tuomi Tiinamaija , Ganna Andrea
Published: April 2024

Type 1 diabetes (T1D) and other autoimmune diseases (AIDs) often co-occur in families. Leveraging data from 58,284 family trios in Finnish nationwide registers (FinRegistry), we identified that, out of 50 parental AIDs examined, 15 were associated with an increased T1D risk in offspring. These identified epidemiological associations were further assessed in 470K genotyped Finns from FinnGen study through comprehensive genetic analyses, partitioned into HLA and non-HLA variations. Using FinnGen’s 12,563 trios, a within-family polygenic transmission analysis demonstrated that the aggregation of many parental AIDs with offspring T1D can be partially explained by HLA and non-HLA polymorphisms in a disease-dependent manner. We, therefore, proposed a parental polygenic score (PGS), incorporating both HLA and non-HLA polymorphisms, to characterize the cumulative risk pattern of T1D in offspring. This raises an intriguing possibility of using parental PGS, in conjunction with clinical diagnoses, to inform individuals about T1D risk in their offspring.
Factors Limiting the Success of an All-Variant COVID-19 Vaccine: A Simulation Study
Authors: Kosinski Robert J.
Published: April 2024

This paper simulates a hypothetical pan-coronavirus vaccine that confers immediate sterilizing immunity against all SARS-CoV-2 variants. Simulations used a SEIIS spreadsheet model that ran two parallel subpopulations: one that accepted vaccination, and another that refused it. The two subpopulations could transmit infections to one another. Using data from the United States (US), the simulated vaccine was tested against limiting factors such as vaccine hesitancy, slow vaccination distribution, and the development of high-transmission variants. The vaccine was often successful at reducing cases, but high-transmission variants and discontinuation of non-pharaceutical interventsions (NPIs) such as masking greatly elevated cases. A puzzling outcome was that if NPIs are discontinued and high-transmission variants become common, the model predicted consistently higher rates of disease than are actually observed in the US in 2024. However, if cumulative exposure to virus antigens increases the duration of immunity or decreases the infectivity of the virus, the model predictions were brought back into a more realistic range. The major finding was that even when a COVID vaccine always produces sterilizing immunity against every SARS-CoV-2 variant, its ability to control the epidemic can be compromised by multiple common conditions.
Multiscale Detrended Cross-Correlation Coefficient: Estimating Coupling in Nonstationary Neurophysiological Signals
Authors: Stylianou Orestis , Susi Gianluca , Hoffmann Martin , Suárez-Méndez Isabel , López-Sanz David , Schirner Michael , Ritter Petra
Published: April 2024

The brain consists of a vastly interconnected network of regions, the connectome. By estimating the statistical interdependence of neurophysiological time series, we can measure the functional connectivity (FC) of this connectome. Pearson’s correlation (rP) is a common metric of coupling in FC studies. YetrPdoes not account properly for the non-stationarity of the signals recorded in neuroimaging. In this study, we introduced a novel estimator of coupled dynamics termed multiscale detrended cross-correlation coefficient (MDC3). Firstly, we showed that MDC3had higher accuracy compared torPusing simulated time series with known coupling, as well as simulated functional magnetic resonance imaging (fMRI) signals with known underlying structural connectivity. Next, we computed functional brain networks based on empirical magnetoencephalography (MEG) and fMRI. We found that by using MDC3we could construct networks of healthy populations with significantly different properties compared torPnetworks. Based on our results, we believe that MDC3is a valid alternative torPthat should be incorporated in future FC studies.

Author Summary

The brain consists of a vastly interconnected network of regions. To estimate the connection strength of such networks the coupling between different brain regions should be calculated. This can be achieved by using a series of statistical methods that capture the connection strength between signals originating across the brain, one of them being Pearson’s correlation (rP). Despite its benefits,rPis not suitable for realistic estimation of brain network architecture. In this study, we introduced a novel estimator called multiscale detrended cross-correlation coefficient (MDC3). Firstly, we showed that MDC3was more accurate thanrPusing simulated signals with known connection strength, as well as simulated brain activity emerging from realistic brain simulations. Next, we constructed brain networks based on real-life brain activity, recorded using two different methodologies. We found that by using MDC3we could construct networks of healthy populations with significantly different properties compared torPnetworks. Based on our results, we believe that MDC3is a valid alternative torPthat should be incorporated in future studies of brain networks.