bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional Status of Pancreatic α and β Cells in Type 2 Diabetes Mellitus Patients with Different Plasma Triglyceride Levels: A Retrospective Analysis
Authors: Guo Hang , Ma Chunlei , Wu Xiaoming , Pan Congqing
Published: August 2021

Objective. To investigate the functional status of pancreatic α and β cells in Type 2 diabetes mellitus (T2DM) patients with different plasma triglyceride (TG) levels. TG levels can be prognostic markers for T2DM. Methods. A total of 328 patients with T2DM were divided into three groups according to different TG levels: the TGL group: TG < 1.7 mmol/L; TGM group: 1.7 mmol/L ≤ TG < 2.3 mmol/L; and TGH group: TG ≥ 2.3 mmol/L. An oral glucose tolerance test (OGTT), insulin release test, and glucagon release test were performed in each patient. The changes of glucagon, glucagon/insulin ratio, early insulin secretion index (

Δ

I

30

/

Δ

G

30

), and area under the insulin curve (AUCI) were compared among each group. Also, the correlations between glucagon and pancreatic β-cell function, glycosylated hemoglobin (HbA1c), and other indices were analyzed. Results. With the increase of TG, the fasting and postprandial glucagon levels, the glucagon/insulin ratio, and the area under the glucagon curve (AUCG) presented an increasing trend. The homeostasis model assessment of insulin resistance (HOMA–IR) of the TGH group was significantly increased compared to the TGL and TGM groups. In addition to the increase in TG levels, the insulin sensitivity index (ISI), homeostasis model assessment for β-cell function index (HOMA-β),

Δ

I

30

/

Δ

G

30

, and AUCI displayed a reducing trend. Glucagon was negatively correlated with

Δ

I

30

/

Δ

G

30

, high-density lipoprotein (HDL), HOMA-β, body mass index (BMI), ISI, and AUCI (

P
<
0.05

) and positively correlated with fasting blood glucose (FPG), AUCG, HOMA-IR, HbA1c, duration, TG, low-density lipoprotein (LDL), and total cholesterol (TC) (

P
<
0.05

). Conclusion. Hypertriglyceridemia aggravated the dysfunction of pancreatic α and β cells. A reasonable control of the TG level makes it easier for blood glucose to reach the standard.
The Emerging Role of Fatty Acid Synthase in Hypoxia‐Induced Pulmonary Hypertensive Mouse Energy Metabolism
Authors: Hou Cuilan , Chen Juan , Zhao Yuqi , Niu Yanhua , Lin Shujia , Chen Shun , Zong Yanfang , Sun Xiaomin , Xie Lijian , Xiao Tingting
Published: August 2021

Aims. This study is aimed at examining whether fatty acid synthase (FAS) can regulate mitochondrial function in hypoxia‐induced pulmonary arterial hypertension (PAH) and its related mechanism. Results. The expression of FAS significantly increased in the lung tissue of mice with hypoxia‐induced PAH, and its pharmacological inhibition by C75 ameliorated right ventricle cardiac function as revealed by echocardiographic analysis. Based on transmission electron microscopy and Seahorse assays, the mitochondrial function of mice with hypoxia was abnormal but was partially reversed after C75 injection. In vitro studies also showed an increase in the expression of FAS in hypoxia‐induced human pulmonary artery smooth muscle cells (HPASMCs), which could be attenuated by FAS shRNA as well as C75 treatment. Meanwhile, C75 treatment reversed hypoxia‐induced oxidative stress and activated PI3K/AKT signaling. shRNA‐mediated inhibition of FAS reduced its expression and oxidative stress levels and improved mitochondrial respiratory capacity and ATP levels of hypoxia‐induced HPASMCs. Conclusions. Inhibition of FAS plays a crucial role in shielding mice from hypoxia‐induced PAH, which was partially achieved through the activation of PI3K/AKT signaling, indicating that the inhibition of FAS may provide a potential future direction for reversing PAH in humans.
PDSS1-Mediated Activation of CAMK2A-STAT3 Signaling Promotes Metastasis in Triple-Negative Breast Cancer
Authors: Yu Tian-Jian , Liu Ying-Ying , Li Xiao-Guang , Lian Bi , Lu Xun-Xi , Jin Xi , Shao Zhi-Ming , Hu Xin , Di Gen-Hong , Jiang Yi-Zhou
Published: August 2021

Genomic alterations are crucial for the development and progression of human cancers. Copy-number gains found in genes encoding metabolic enzymes may induce triple-negative breast cancer (TNBC) adaptation. However, little is known about how metabolic enzymes regulate TNBC metastasis. Using our previously constructed multiomic profiling of a TNBC cohort, we identified decaprenyl diphosphate synthase subunit 1 (PDSS1) as an essential gene for TNBC metastasis. PDSS1 expression was significantly upregulated in TNBC tissues compared with adjacent normal tissues and was positively associated with poor survival among patients with TNBC. PDSS1 knockdown inhibited TNBC cell migration, invasion, and distant metastasis. Mechanistically, PDSS1, but not a catalytically inactive mutant, positively regulated the cellular level of coenzyme Q10 (CoQ10) and intracellular calcium levels, thereby inducing CAMK2A phosphorylation, which is essential for STAT3 phosphorylation in the cytoplasm. Phosphorylated STAT3 entered the nucleus, promoting oncogenic STAT3 signaling and TNBC metastasis. STAT3 phosphorylation inhibitors (e.g., Stattic) effectively blocked PDSS1-induced cell migration and invasion in vitro and tumor metastasis in vivo. Taken together, our study highlights the importance of targeting the previously uncharacterized PDSS1/CAMK2A/STAT3 oncogenic signaling axis, expanding the repertoire of precision medicine in TNBC.

Significance:

A novel metabolic gene PDSS1 is highly expressed in triple-negative breast cancer tissues and contributes to metastasis, serving as a potential therapeutic target for combating metastatic disease.
Upregulation of C/EBPα Inhibits Suppressive Activity of Myeloid Cells and Potentiates Antitumor Response in Mice and Patients with Cancer
Authors: Hashimoto Ayumi , Sarker Debashis , Reebye Vikash , Jarvis Sheba , Sodergren Mikael H. , Kossenkov Andrew , Sanseviero Emilio , Raulf Nina , Vasara Jenni , Andrikakou Pinelopi , Meyer Tim , Huang Kai-Wen , Plummer Ruth , Chee Cheng E. , Spalding Duncan , Pai Madhava , Khan Shahid , Pinato David J. , Sharma Rohini , Basu Bristi , Palmer Daniel , Ma Yuk-Ting , Evans Jeff , Habib Robert , Martirosyan Anna , Elasri Naouel , Reynaud Adeline , Rossi John J. , Cobbold Mark , Habib Nagy A. , Gabrilovich Dmitry I.
Published: August 2021

Purpose:

To evaluate the mechanisms of how therapeutic upregulation of the transcription factor, CCAAT/enhancer-binding protein alpha (C/EBPα), prevents tumor progression in patients with advanced hepatocellular carcinoma (HCC) and in different mouse tumor models.

Experimental Design:

We conducted a phase I trial in 36 patients with HCC (NCT02716012) who received sorafenib as part of their standard care, and were given therapeutic C/EBPα small activating RNA (saRNA; MTL-CEBPA) as either neoadjuvant or adjuvant treatment. In the preclinical setting, the effects of MTL-CEBPA were assessed in several mouse models, including BNL-1ME liver cancer, Lewis lung carcinoma (LLC), and colon adenocarcinoma (MC38).

Results:

MTL-CEBPA treatment caused radiologic regression of tumors in 26.7% of HCC patients with an underlying viral etiology with 3 complete responders. MTL-CEBPA treatment in those patients caused a marked decrease in peripheral blood monocytic myeloid-derived suppressor cell (M-MDSC) numbers and an overall reduction in the numbers of protumoral M2 tumor-associated macrophages (TAM). Gene and protein analysis of patient leukocytes following treatment showed CEBPA activation affected regulation of factors involved in immune-suppressive activity. To corroborate this observation, treatment of all the mouse tumor models with MTL-CEBPA led to a reversal in the suppressive activity of M-MDSCs and TAMs, but not polymorphonuclear MDSCs (PMN-MDSC). The antitumor effects of MTL-CEBPA in these tumor models showed dependency on T cells. This was accentuated when MTL-CEBPA was combined with checkpoint inhibitors or with PMN-MDSC–targeted immunotherapy.

Conclusions:

This report demonstrates that therapeutic upregulation of the transcription factor C/EBPα causes inactivation of immune-suppressive myeloid cells with potent antitumor responses across different tumor models and in cancer patients. MTL-CEBPA is currently being investigated in combination with pembrolizumab in a phase I/Ib multicenter clinical study (NCT04105335).
Relevance of pRB Loss in Human Malignancies
Authors: Mandigo Amy C. , Tomlins Scott A. , Kelly William K. , Knudsen Karen E.
Published: August 2021

The retinoblastoma tumor suppressor protein (pRB) is a known regulator of cell-cycle control; however, recent studies identified critical functions for pRB in regulating cancer-associated gene networks that influence the DNA damage response, apoptosis, and cell metabolism. Understanding the impact of these pRB functions on cancer development and progression in the clinical setting will be essential, given the prevalence of pRB loss of function across disease types. Moreover, the current state of evidence supports the concept that pRB loss results in pleiotropic effects distinct from tumor proliferation. Here, the implications of pRB loss (and resultant pathway deregulation) on disease progression and therapeutic response will be reviewed, based on clinical observation. Developing a better understanding of the pRB-regulated pathways that underpin the aggressive features of pRB-deficient tumors will be essential for further developing pRB as a biomarker of disease progression and for stratifying pRB-deficient tumors into more effective treatment regimens.
Circulating and Intratumoral Adrenal Androgens Correlate with Response to Abiraterone in Men with Castration-Resistant Prostate Cancer
Authors: Mostaghel Elahe A. , Marck Brett T. , Kolokythas Orpheus , Chew Felix , Yu Evan Y. , Schweizer Michael T. , Cheng Heather H. , Kantoff Phillip W. , Balk Steven P. , Taplin Mary-Ellen , Sharifi Nima , Matsumoto Alvin M. , Nelson Peter S. , Montgomery R. Bruce
Published: August 2021

Purpose:

In metastatic castration-resistant prostate cancer (mCRPC) low serum androgens prior to starting abiraterone acetate (AA) is associated with more rapid progression. We evaluated the effect of AA on androgens in castration-resistant prostate cancer (CRPC) metastases and associations of intratumoral androgens with response.

Experimental Design:

We performed a phase II study of AA plus prednisone in mCRPC. The primary outcome was tissue testosterone at 4 weeks. Exploratory outcomes were association of steroid levels and genomic alterations with response, and escalating AA to 2,000 mg at progression.

Results:

Twenty-nine of 30 men were evaluable. Testosterone in metastatic biopsies became undetectable at 4 weeks (P < 0.001). Serum and tissue dehydroepiandrosterone sulfate (DHEAS) remained detectable in many patients and was not increased at progression. Serum and tissue DHEAS in the lowest quartile (pretreatment), serum DHEAS in the lowest quartile (4 weeks), and undetectable tissue DHEAS (on-therapy) associated with rapid progression (20 vs. 48 weeks, P = 0.0018; 20 vs. 52 weeks, P = 0.0003; 14 vs. 40 weeks, P = 0.0001; 20 vs. 56 weeks, P = 0.02, respectively). One of 16 men escalating to 2,000 mg had a 30% PSA decline; 13 developed radiographic progression by 12 weeks. Among patients with high serum DHEAS at baseline, wild-type (WT) PTEN status associated with longer response (61 vs. 33 weeks, P = 0.02).

Conclusions:

Low-circulating adrenal androgen levels are strongly associated with an androgen-poor tumor microenvironment and with poor response to AA. Patients with CRPC with higher serum DHEAS levels may benefit from dual androgen receptor (AR)-pathway inhibition, while those in the lowest quartile may require combinations with non–AR-directed therapy.
Ex vivo Fusion Confocal Microscopy of Colorectal Polyps: A Fast Turnaround Time of Pathological Diagnosis
Authors: Guerrero Jose Andres , Pérez-Anker Javiera , Fernández-Esparrach Gloria , Archilla Ivan , Diaz Alba , Lopez-Prades Sandra , Rodrigo-Calvo Maite , Lahoz Sara , Camps Jordi , Puig Susana , Malvehy Josep , Cuatrecasas Miriam
Published: August 2021

Background: Colorectal cancer screening programs have accomplished a mortality reduction from the disease but have created bottlenecks in endoscopy units and pathology departments. We aimed to explore the feasibility of ex vivo fusion confocal microscopy (FuCM) to improve the histopathology diagnostic efficiency and reduce laboratory workload. Methods: Consecutive fresh polyps removed at colonoscopy were scanned using ex vivo FuCM, then went through histopathologic workout and hematoxylin and eosin (H&E) diagnosis. Two pathologists blinded to H&E diagnosis made a diagnosis based on FuCM scanned images. Results: Thirty-six fresh polyps from 22 patients were diagnosed with FuCM and H&E. Diagnostic agreement between H&E and FuCM was 97.2% (kappa = 0.96) for pathologist #1 and 91.7% (kappa = 0.87) for pathologist #2. Diagnostic performance concordance between FuCM and H&E to discern adenomatous from nonadenomatous polyps was 100% (kappa = 1) for pathologist #1 and 97.2% (kappa = 0.94) for pathologist #2. Global interobserver agreement was 94.44% (kappa = 0.91) and kappa = 0.94 to distinguish adenomatous from nonadenomatous polyps. Conclusions: Ex vivo FuCM shows an excellent correlation with standard H&E for the diagnosis of colorectal polyps. The clinical direct benefit for patients, pathologists, and endoscopists allows adapting personalized surveillance protocols after colonoscopy and a workload decrease in pathology departments.
Hemoperfusion with CytoSorb® in Critically Ill COVID-19 Patients
Authors: Peng Jin-Yu , Li Lu , Zhao Xu , Ding Feng , Hou Xiaotong , Peng Zhiyong
Published: August 2021

Introduction: Systematic inflammatory response occurred in some critically ill patients with COVID-19. Cytokine reduction by hemadsorption is a mechanism of treatment. However, whether CytoSorb hemoperfusion works for critically ill COVID-19 patients remains unknown. Materials and Methods: We observed case series of critically ill COVID-19 patients receiving CytoSorb hemoperfusion as rescue therapy from 3 hospitals in Hubei, China from February 28, 2020, to April 7, 2020. Their demographic, laboratory, and clinical data were collected. The parameters for organ function and IL-6 levels were compared before and after treatments. Results: A total of 10 cases were included. The median age of the patients was 67.7 years (range = 50–85) with APACHE II (23.5) and SOFA (11.4). Patients received a median of 3 attempts of hemoperfusion (range = 1–6). The median CytoSorb perfusion time was 47 h (12–92 h). The level of IL-6 significantly decreased after treatments (712.6 [145–5,000] vs. 136.7 [46.3–1,054] pg/mL, p = 0.005). Significant improvement was found in PaO2/FiO2 (118 [81–220] vs. 163 [41–340] mm Hg, p = 0.04) and lactate levels (2.5 [1–18] vs. 1.7 [1.1–10] mmol/L, p = 0.009). The hemodynamics measured by norepinephrine/MAP slightly improved after treatment (17 [0–68] vs. 8 [0–39], p = 0.09). Albumin mildly decreased after CytoSorb. No significant changes were found in red blood cell counts, white cell counts, and platelets. Conclusion: Treatment with CytoSorb in critically ill COVID-19 patients was associated with decreased IL-6 improvement in oxygenation. However, these effects cannot be confirmed as the direct effects of CytoSorb owing to lack of controls. Establishing causality requires large-scale randomized clinical trials.
Cognitive Failures and the Role of Emotion in Dimensional Schizotypy: A Replication and Extension
Authors: Alvarez Emmanuel E. , Pujji Sherry D. , Dinzeo Thomas J.
Published: August 2021

Introduction: Cognitive failures are commonplace within the general population but may be particularly heightened in those with higher levels of schizotypy. This is especially salient in the context of enduring trait and momentary state negative emotion which often contributes to increases in daily impairments, leading to a more debilitating and distracted life. Particularly, individuals with elevated levels of schizotypy may be more likely to experience cognitive failures, especially in the presence of negative trait emotion such as depression, anxiety, and stress. However, little is known about the influence of state emotion and the distinct roles that state and trait emotion may have with cognitive failures and schizotypy. Methods: To replicate and extend previous findings, 306 (58% males) undergraduate students aged 18–50 years (M = 19.343; SD = 2.493) completed self-report measures of cognitive failures, trait and state emotion, and schizotypy. Mediation and moderation analyses were performed in SPSS to examine the potential effects of trait and state emotion on the relationship between schizotypy and cognitive failures. Results: Consistent with previous findings, mood symptomology, in addition to negative affect, mediated cognitive failures in those with higher levels of schizotypy. However, in our sample, positive affect did not appear to buffer against cognitive failures. Conclusion: The findings of the present study suggest there may be a nuanced relationship between both negative trait and state emotions on the relationships between cognitive failures and schizotypy. Understanding the interaction of enduring versus momentary emotion on cognition as they relate to an elevated risk for developing schizophrenia-spectrum phenomena may be a point for earlier and more targeted interventions.
Factors Associated with Nonattendance to a Geriatric Clinic among Mexican Older Adults
Authors: Negrete-Najar Juan Pablo , Juárez-Carrillo Yoselin , Gómez-Camacho Jimena , Mejía-Domínguez Nancy R. , Soto-Perez-de-Celis Enrique , Avila-Funes Jose Alberto , Navarrete-Reyes Ana Patricia
Published: August 2021

Introduction: Outpatient appointment nonattendance (NA) represents a public health problem, increasing the risk of unfavorable health-related outcomes. Although NA is significant among older adults, little is known regarding its correlates. This study aimed to identify the correlates (including several domains from the geriatric assessment) of single and repeated NA episodes in a geriatric medicine outpatient clinic, in general and in the context of specific comorbidities. Methods: This is a cross-sectional study including data from 3,034 older adults aged ≥60 years with ≥1 scheduled appointments between January 1, 2016, and December 31, 2016. Appointment characteristics as well as sociodemographic, geographical, and environmental information were obtained. Univariate and multivariate multinomial regression analyses were carried out. Results: The mean age was 81.8 years (SD 7.19). Over a third (37.4%) of participants missed one scheduled appointment, and 14.4% missed ≥2. Participants with a history of stroke (OR 1.336, p = 0.041) and those with a greater number of scheduled appointments during the study time frame (OR 1.182, p < 0.001) were more likely to miss one appointment, while those with Parkinson’s disease (OR 0.346, p < 0.001), other pulmonary diseases (OR 0.686, p = 0.008), and better functioning for activities of daily living (ADL) (OR 0.883, p < 0.001) were less likely to do so. High socioeconomic level (OR 2.235, p < 0.001), not having a partner (OR 1.410, p = 0.006), a history of fractures (OR 1.492, p = 0.031), and a greater number of scheduled appointments (OR 1.668, p < 0.001) increased the risk of repeated NA, while osteoarthritis (OR 0.599, p = 0.001) and hypertension (OR 0.680, p = 0.002) decreased it. In specific comorbidity populations (hypertension, type 2 diabetes mellitus, and cancer), better ADL functioning protected from a single NA, while better mobility functioning protected from repeated NA in older patients with hypertension and cancer. Discussion/Conclusion: Identifying geriatric factors linked to an increased probability of NA may allow one to anticipate its likelihood and lead to the design and implementation of preventive strategies and to an optimization of the use of available health resources. The impact of these factors on adherence to clinical visits requires further investigation.
Berberine Improves the Symptoms of DHEA-Induced PCOS Rats by Regulating Gut Microbiotas and Metabolites
Authors: Shen Hao-Ran , Xu Xiao , Ye Dan , Li Xue-Lian
Published: August 2021

Objectives: The aim of this study was to investigate the effects of berberine on polycystic ovary syndrome (PCOS) with insulin resistance (IR). Design: This study performed 16S rRNA sequencing and metabolomic analysis on dehydroepiandrosterone (DHEA)-induced PCOS rats treated with berberine, focusing on the improvement of PCOS-IR by modifying gut microbiota and metabolism. Methods: Forty-two female Sprague Dawley rats were randomly divided into 4 experimental groups of 8 rats each (PCOS + HFD, PCOS + HFD + BBR, NCD + PCOS, and NCD + PCOS + BBR groups). Homeostasis model assessment of insulin resistance (HOMA-IR) index-related indicators and hormone level in serum were analyzed. 16S rRNA sequencing and metabolomic analysis were performed on DHEA-induced PCOS rats treated with berberine. In addition, the differential microbiotas and metabolites were screened. Also, enrichment analysis was carried out on the differential metabolites. Finally, we constructed a correlation network to analyze the correlation between differential microbiotas and metabolites. Results: Firmicutes and Bacteroidetes were changed at the phylum level, and Romboutsia, Bacteroides, and Clostridium_sensu_stricto_1 were changed at the genus level after berberine treatment. In addition, a total of 26 differential operational taxonomic units and 3 metabolites (glutamine, unsaturated acids [CH = CH], and glucose) between 2 groups were obtained. Moreover, these metabolites were mainly involved in type 2 diabetes mellitus, 2-component system, and ABC transporter Kyoto Encyclopedia of Genes and Genomes pathways. And, 3 microbiotas (Lachnospiraceae_NC2004_group, Flavonifractor, and Parasutterella) were regulated by glucose and glutamine. Limitations: The sample size involved in this study is relatively small. In addition, relevant experiments need to be performed to verify the obtained results from this study, and in-depth functional studies are needed. Conclusions: Berberine is effective in improving the pathological condition in PCOS by regulating the gut microbiotas and metabolites. This study will provide evidence for therapeutic efforts to treat PCOS-IR using berberine.
Use of Antibiotics during Immune Checkpoint Inhibitor Treatment Is Associated with Lower Survival in Hepatocellular Carcinoma
Authors: Cheung Ka Shing , Lam Lok Ka , Seto Wai Kay , Leung Wai K.
Published: August 2021

Background: Recent studies suggested that use of antibiotics may interfere with treatment responses to immune checkpoint inhibitors (ICIs). We determined whether concurrent use of antibiotics during ICI therapy was associated with adverse outcomes in patients with advanced hepatocellular carcinoma (HCC). Methods: This is a territory-wide retrospective cohort study including all advanced HCC patients who received ICIs (nivolumab, pembrolizumab, or ipilimumab) between January 2014 and December 2019. Exclusion criteria included prior liver transplantation and use of cabozantinib, regorafenib, or ramucirumab. The exposure of interest was concurrent antibiotic use within 30 days before or after the commencement of ICI. The adjusted hazard ratio (aHR) of cancer-related mortality and all-cause mortality with antibiotic use was derived by propensity score (PS) matching in 1:2 ratio of covariates including baseline characteristics, causes of cirrhosis, Child-Pugh status, prior HCC treatment, comorbidities, concurrent medications, and laboratory results including alpha fetoprotein. Results: A total of 395 HCC patients who had received ICIs were included. During a median follow-up of 16.5 months (interquartile range [IQR]: 5.6–44.3), there were 286 (72.4%) deaths including 231 cancer-related deaths. The median time from the first ICI to event was 7.7 months (IQR: 4.0–16.8). PS matching of 56 antibiotic users with 99 nonusers showed that concurrent antibiotic use with ICI was associated with higher cancer-related (aHR: 1.66; 95% CI: 1.08–2.54) and all-cause mortality (aHR: 1.63; 95% CI: 1.17–2.28). Conclusions: Concurrent antibiotic use during immunotherapy was associated with higher mortality in patients with advanced HCC. Further studies should examine the role of gut dysbiosis on responses to ICI.
Assessment of Endoscopic Disease Activity in Ulcerative Colitis: Is Simplicity the Ultimate Sophistication?
Authors: Sharara Ala I. , Malaeb Maher , Lenfant Matthias , Ferrante Marc
Published: August 2021

Background: Endoscopic remission is an increasingly recognized important therapeutic endpoint in the management of patients with UC. Summary: The Mayo Endoscopic Score (MES) remains the most common endoscopic index recommended in guidelines and widely used in clinical trials and in clinical practice. The MES is easy, simple, and practical but is suboptimal at providing an accurate depiction of segmental healing and/or at measuring a substantial but incomplete response across the spectrum of endoscopic inflammation. Other endoscopic scores have been proposed but have not received wide recognition or adoption.
Filamin C Cardiomyopathy Variants Cause Protein and Lysosome Accumulation
Authors: Agarwal Radhika , Paulo Joao A. , Toepfer Christopher N. , Ewoldt Jourdan K. , Sundaram Subramanian , Chopra Anant , Zhang Qi , Gorham Joshua , DePalma Steven R. , Chen Christopher S. , Gygi Steven P. , Seidman Christine E. , Seidman J.G.
Published: August 2021

Rationale:

Dominant heterozygous variants in filamin C (
FLNC
) cause diverse cardiomyopathies, although the underlying molecular mechanisms remain poorly understood.

Objective:

We aimed to define the molecular mechanisms by which
FLNC
variants altered human cardiomyocyte gene and protein expression, sarcomere structure, and contractile performance.

Methods and Results:

Using CRISPR/Cas9, we introduced
FLNC
variants into human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs). We compared isogenic hiPSC-CMs with normal (wild-type), ablated expression (
FLNC
−/−
), or haploinsufficiency (
FLNC
+/−
) that causes dilated cardiomyopathy. We also studied a heterozygous in-frame deletion (
FLNC
+/Δ7aa
) which did not affect FLNC expression but caused aggregate formation, similar to
FLNC
variants associated with hypertrophic cardiomyopathy.
FLNC
−/−
hiPSC-CMs demonstrated profound sarcomere misassembly and reduced contractility. Although sarcomere formation and function were unaffected in
FLNC
+/
−
and
FLNC
+/Δ7aa
hiPSC-CMs, these heterozygous variants caused increases in lysosome content, enhancement of autophagic flux, and accumulation of FLNC-binding partners and Z-disc proteins.

Conclusions:

FLNC expression is required for sarcomere organization and physiological function. Variants that produce misfolded FLNC proteins cause the accumulation of FLNC and FLNC-binding partners which leads to increased lysosome expression and activation of autophagic pathways. Surprisingly, similar pathways were activated in
FLNC
haploinsufficient hiPSC-CMs, likely initiated by the loss of stoichiometric FLNC protein interactions and impaired turnover of proteins at the Z-disc. These results indicate that both
FLNC
haploinsufficient variants and variants that produce misfolded FLNC protein cause disease by similar proteotoxic mechanisms and indicate the therapeutic potential for augmenting protein degradative pathways to treat a wide range of
FLNC
-related cardiomyopathies.
Rare
NOTCH3
Variants in a Chinese Population-Based Cohort and Its Relationship With Cerebral Small Vessel Disease
Authors: Liu Jing-Yi , Yao Ming , Dai Yi , Han Fei , Zhai Fei-Fei , Zhang Ding-Ding , Zhou Li-Xin , Ni Jun , Zhang Shu-Yang , Cui Li-Ying , Zhu Yi-Cheng
Published: August 2021

Background and Purpose:

Researches on rare variants of
NOTCH3
in the general Chinese population are lacking. This study aims to describe the spectrum of rare
NOTCH3
variants by whole-exome sequencing in a Chinese community-based cohort and to investigate the association between rare
NOTCH3
variants and age-related cerebral small vessel disease.

Methods:

The cross-sectional study comprised 1065 participants who underwent whole-exome sequencing and brain magnetic resonance imaging.
NOTCH3
variants with minor allele frequency<1% in all 4 public population databases (1000 Genomes, ESP6500siv2_ALL, GnomAD_ALL, and GnomAD_EAS) were defined as rare variants. Multivariable linear and logistic regressions were used to investigate the associations between rare
NOTCH3
variants and volume of white matter hyperintensities and cerebral small vessel disease burden. Clinical and imaging characteristics of rare
NOTCH3
variant carriers were summarized.

Results:

Sixty-five rare
NOTCH3
variants were identified in 147 of 1065 (13.8%) participants, including 57 missense single nucleotide polymorphisms (SNPs), 5 SNPs in splice branching sites, and 3 frameshift deletions. A significantly higher volume of white matter hyperintensities and heavier burden of cerebral small vessel disease was found in carriers of rare
NOTCH3
EGFr (epidermal growth factor-like repeats)-involving variants, but not in carriers of EGFr-sparing variants. The carrying rate of rare EGFr-involving
NOTCH3
variants in participants with dementia or stroke was significantly higher than those without dementia or stroke (12.4% versus 6.6%,
P
=0.041). Magnetic resonance imaging signs suggestive of CADASIL were found in 3.4% (5/145) rare EGFr cysteine-sparing
NOTCH3
variant carriers but not in 2 cysteine-altering
NOTCH3
variant carriers.

Conclusions:

Carriers of rare
NOTCH3
variants involving the EGFr domain may be genetically predisposed to age-related cerebral small vessel disease in the general Chinese population.
Hippocampal–Cortical Encoding Activity Predicts the Precision of Episodic Memory
Authors: Korkki Saana M. , Richter Franziska R. , Simons Jon S.
Published: August 2021

Our recollections of past experiences can vary in both the number of specific event details accessible from memory and the precision with which such details are reconstructed. Prior neuroimaging evidence suggests the success and precision of episodic recollection to rely on distinct neural substrates during memory retrieval. In contrast, the specific encoding mechanisms supporting later memory precision, and whether they differ from those underlying successful memory formation in general, are currently unknown. Here, we combined continuous measures of memory retrieval with model-based analyses of behavioral and neuroimaging data to tease apart the encoding correlates of successful memory formation and mnemonic precision. In the MRI scanner, participants encoded object-scene displays and later reconstructed features of studied objects using a continuous scale. We observed overlapping encoding activity in inferior prefrontal and posterior perceptual regions to predict both which object features were later remembered versus forgotten and the precision with which they were reconstructed from memory. In contrast, hippocampal encoding activity significantly predicted the precision, but not overall success, of subsequent memory retrieval. The current results align with theoretical accounts proposing the hippocampus to be critical for representation of high-fidelity associative information and suggest a contribution of shared cortical encoding mechanisms to the formation of both accessible and precise memory representations.
Overlapping Neuronal Population Responses in the Human Parietal Cortex during Visuospatial Attention and Arithmetic Processing
Authors: Liu Nan , Pinheiro-Chagas Pedro , Sava-Segal Clara , Kastner Sabine , Chen Qi , Parvizi Josef
Published: August 2021

Engagement of posterior parietal cortex (PPC) in visuospatial attention and arithmetic processing has been extensively documented using neuroimaging methods. Numerous studies have suggested a close connection between visuospatial attention and arithmetic processing. However, the extant evidence in humans stems from neuroimaging methods that have relied on group analyses without much knowledge about the profile of neurophysiological engagement within localized neuronal populations at the individual brain level. Hence, it has remained unclear if the overlap of two functions in the PPC is the product of averaging, or they truly stem from a common profile of activity within the same neuronal populations in the human PPC. In the current study, we leveraged the anatomical precision and high signal-to-noise ratio of intracranial electrocorticography and probed the engagement of discrete PPC neuronal populations in seven neurosurgical patients (n = 179 total PPC sites covered; 26 sites on average per individual participant). We aimed to study the extent of parietal activations within each individual brain during visuospatial attention versus arithmetic tasks and the profile of electrophysiological responses within a given recording site during these tasks. Our findings indicated that about 40% of PPC sites did not respond to either visuospatial attention or arithmetic stimuli—or episodic memory conditions that were used as an adjunct control condition. Of those that were activated during either visuospatial attention or arithmetic conditions, a large majority showed overlapping responses during both visuospatial attention and arithmetic conditions. Most interestingly, responses during arithmetic processing were greatest in sites along the intraparietal sulcus region showing preference to contralateral, instead of ipsilateral, visual probes in the visuospatial attention task. Our results provide novel data about the relationship between numerical and spatial orientation at the neuronal population level and shed light on the complex functional organization of the PPC that could not be attained with noninvasive methods.
Taxonomic notes on subgenus Steneotarsonemoides (Acari: Tarsonemidae) with description of a new species of Steneotarsonemus from Tiger grass in the northern hill zone of West Bengal, India
Authors: GANGULY MOUMI , MONDAL PRIYANKAR , KARMAKAR KRISHNA
Published: August 2021

A new species of tarsonemid mite, Steneotarsonemus amlisoae sp. nov. collected from tiger grass Thysanolaena latifolia (Poaceae) is described with illustrations of adult female, male and larva. The new species is the fourth species of Steneotarsonemus described from India. The species shares a lot of similarities with S. konoi but differ by apodeme architecture, cheliceral structure, setal length and positions. A taxonomic note on subgenus Steneotarsonemoides is provided.
Longitudinal Clinical and Patient-Reported Outcomes After Transversus Abdominis Release for Complex Hernia Repair With a Review of the Literature
Authors: Christopher Adrienne N. , Morris Martin P. , Barrette Louis-Xavier , Patel Viren , Broach Robyn B. , Fischer John P.
Published: August 2021

Purpose

Posterior component separation with transversus abdominis release (TAR) enables medial myofascial flap advancement in complex abdominal wall reconstruction. Here, we add to a growing body of literature on TAR by assessing longitudinal clinical and patient-reported outcomes (PROs) after complex ventral hernia repair (VHR) with TAR.

Methods

Adult patients undergoing VHR with TAR between 10/15/2015 and 1/15/2020 were retrospectively identified. Patients with parastomal hernias and <12 months of follow-up were excluded. Clinical outcomes and PROs were assessed.

Results

Fifty-six patients were included with a median age and body mass index of 60 and 30.8 kg/m2, respectively. The average hernia defect was 384 cm2 [IQR 205-471], and all patients had retromuscular mesh placed. The most common complications were delayed healing (19.6%) and seroma (14.3%). There were no cases of mesh infection or explantation. Previous hernia repair and concurrent panniculectomy were risk factors for developing complications ( P < .05). One patient (1.8%) recurred at a median follow-up of 25.2 months [IQR 18.2-42.4]. Significant improvement in disease-specific PROs was maintained throughout the follow-up period (before to after P < .05).

Conclusion

Transversus abdominis release is a safe and efficacious technique to achieve fascial closure and retromuscular mesh in the repair of complex hernia defects.
Decreased Facial Emotion Recognition in Elderly Patients With Hearing Loss Reflects Diminished Social Cognition
Authors: Saatci Özlem , Geden Hakan , Güneş Çiftçi Halide , Çiftçi Zafer , Arıcı Düz Özge , Yulug Burak
Published: August 2021

Objective:

The main objective of this research was to evaluate the correlation between the severity of hearing loss and the facial emotional recognition as a critical part of social cognition in elderly patients.

Methods:

The prospective study was comprised of 85 individuals. The participants were divided into 3 groups. The first group consisted of 30 subjects older than 65 years with a bilateral pure-tone average mean >30 dB HL. The second group consisted of 30 subjects older than 65 years with a PTA mean ≤30 dB HL. The third group consisted of 25 healthy subjects with ages ranging between 18 and 45 years and a PTA mean ≤25 dB HL. A Facial Emotion Identification Test and a Facial Emotion Discrimination Test were administered to all groups.

Results:

Elderly subjects with hearing loss performed significantly worse than the other 2 groups on the facial emotion identification and discrimination tests ( P < .05). Appealingly, they identified a positive emotion, “happiness,” more accurately in comparison to the other negative emotions.

Conclusions:

Our results suggest that increased age might be associated with decreased facial emotion identification and discrimination scores, which could be deteriorated in the presence of significant hearing loss.
Transformations of the Cambridge Critique
Authors: Schefold Bertram
Published: August 2021

The debate on capital theory has recently been revived. Reswitching had led to agnosticism regarding the substitution of capital for labour in consequence of changes in the rate or profit. The paradoxes of reswitching and reverse capital deepening now turn out to be rare for theoretical reasons, and this is confirmed empirically, but new results also show that the possibilities of substitution between capital and labour are quite limited; their ratio is given within narrow limits by technology, if the choice of techniques is efficient. This is a new critique of neoclassical theory; it confirms the complementary theories of distribution advanced by the Cambridge economists: the share of profits is influenced by effective demand (Kaldor) and by the level of interest rates as an element of cost (Sraffa). Both theories presuppose the stability of the capital-output ratio. This finding also sheds light on the options of central banks regarding the fixation of interest rates.

JEL Code: B51, C67, D57, E11, E13, E44
Estimating farmers’ internal value of crop residues in smallholder crop-livestock systems: A South Asia case study
Authors: Olson Kent , Gauto Victor , Teufel Nils , Swain Braja , Tui Sabine Homann-Kee , Duncan Alan , Erenstein Olaf
Published: August 2021

Crop residues (CR) are an important, internally produced resource with several uses on smallholder, mixed crop-livestock farms, including livestock feed, mulch, fuel and construction material. This study sets out to develop a method to estimate the internal shadow value of CR as feed and as mulch for smallholder households. The study uses a South Asia case study as illustration using data from a set of village and household surveys in three different sites. The estimated shadow prices were higher for CR as mulch than for CR as feed at all three sites. These results reject the null hypothesis that the estimated shadow price for CR as feed is greater than the shadow price for CR as mulch. Since the null hypothesis was formed based on observing household behavior, the rejection of the null hypothesis implies that there are other reasons to explain why more households use CR as feed versus as mulch.
Screening Youth Soccer Players by Means of Cognitive Function and Agility Testing
Authors: Lovecchio Nicola , Manes Gianluca , Filipas Luca , Giuriato Matteo , Torre Antonio La , Iaia F. Marcello , Codella Roberto
Published: August 2021

Talent identification in sports is a heavily debated topic. Previous studies have separately explored either executive functions or gross motor skills to predict the success of top-level soccer players or, more generally, to characterize elite performance in soccer. However, at mid-childhood, the possibility to scope sport-specific requirements remains elusive. We aimed in this study to investigate a valid and simple method of testing for a unique combination of cognitive and speed abilities for identifying promising soccer players at mid-childhood. We measured cognitive functions by means of a Stroop smartphone application and agility with a T-Drill Ball-success test, in two groups of (a) elite- ( n = 31) and (b) low-division ( n = 37) Italian 7-year-old male soccer players. We administered the tests in a randomized order to both groups. We found better inhibitory control, cognitive flexibility and soccer-specific agility in high-division versus low-division players ( p < .001). Inhibitory response and agility were positively associated with the augmented quality of the performance from low-division players to high-division players ( r = .55; p = .0001). These results suggest that, even at an early age, cognitive control together with soccer-specific skills is associated with better performance.
The Roles of Grit and Motivation in Predicting Children’s Leisure-Time Physical Activity: One-Year Effects
Authors: Hein Vello , Koka Andre , Tilga Henri , Kalajas-Tilga Hanna , Raudsepp Lennart
Published: August 2021

In this study, we tested two alternative models for investigating the ability of dimensions of personal grit (consistency of interest and perseverance of effort) and autonomous motivation to predict the leisure-time physical activity (LTPA) over a one-year period of 256 youth (aged 11-15 years at the beginning of the study). Specifically, we compared a model in which dimensions of grit were assumed to predict LTPA through autonomous motivation with a model in which autonomous motivation was assumed to predict LTPA through dimensions of grit. We tested the two models using variance-based structural equation modelling with Warp PLS v7.0 software. Both models showed a good fit with the data and equally explained 41% of the variance in LTPA over this one-year time period. However, the model based on the total effect of autonomous motivation (β = 0.448, p < 0.001, ES = 0.229) on LTPA through the dimensions of grit was stronger than the model based on the total effect of perseverance of effort (β = 0.356, p < 0.001, ES = 0.126) on LTPA through autonomous motivation, and the total effect of consistency of interest was not significant (β = −0.029, p > 0.05, ES = 0.003). Our findings underscore the relatively greater importance of the interplay between autonomous motivation and perseverance of effort, versus consistency of interest, in predicting LTPA among youth over a one-year period.
Effects of Mental Fatigue Induced by Social Media Use on Volleyball Decision-Making, Endurance, and Countermovement Jump Performance
Authors: Fortes Leonardo S. , Fonseca Fabiano S. , Nakamura Fabio Y. , Barbosa Bruno Teixeira , Gantois Petrus , de Lima-Júnior Dalton , Ferreira Maria E. C.
Published: August 2021

We studied the effects of repeated inducements of mental fatigue (MF) from using social media on smartphones immediately before training sessions by young male volleyball athletes, focusing specifically on their decision-making, endurance, and countermovement jump performance (CMJ). We pair-matched 24 participants according to their decision-making abilities and then, randomly assigned them to one of two 4-week block training groups: control (CON) and smartphone use (SMA). For a 30-minute period before each training session, the CON group watched TV and the SMA group used social media apps on smartphones. We found a significant group x time interaction effect for decision making (attack, p = 0.03; passing, p = 0.02) during training blocks. More specifically, only the CON group improved their decision making (attack, p = 0.03; passing, p = 0.02). Both groups significantly improved their CMJ performance ( p = .01), with no significant group x time interaction effect for CMJ ( p = 0.91). Neither group significantly improved their endurance ( p = 0.56). We concluded that 30-minutes of repetitive social media app use on a smartphone immediately before 4-weeks of volleyball training sessions negatively affected decision-making in young male volleyball athletes.
Emergence of Frequency-Dependent Motor Variability Within Supra-Second Auditory Cueing
Authors: Sanjram Premjit Khanganba , Shivhare Yogesh Kumar
Published: August 2021

Motor variability (MV) is an essential feature of the sensory motor system, and it plays an important role in sensory-motor learning. MV facilitates motor adaptation during auditory-motor synchronization (AMS). In AMS, individuals receive a series of similar auditory stimuli that come in a periodic manner at a fixed interval called an inter-stimulus interval (ISI). Peri-second ISI (1 second range) and supra-second ISI (>1 second) are differently processed, since these intervals involve different amount of cognitive resources. Supra-second ISI involves more top-down attention as compared to peri-second ISI. In this study we examined the effect of tone frequency (perceptual property of auditory stimuli) on predictive tapping and MV under peri-second and supra-second ranges. We examined the effect of tone frequency (a perceptual property of auditory stimuli) on predictive tapping and motor variability (MV) under short (peri-second) and long (supra-second) inter-stimulus intervals. Among 30 healthy participants (aged 18–35 years, M = 24.6 years), we randomly assigned equal numbers of these two inter-stimulus conditions to isochronous sound sequences. In their attempt to synchronize their motor responses with the tone, participants reproduced the ISI in their inter-tap intervals (ITIs). We analyzed their predictive tapping in terms of negative asynchrony (in which the tap occurs before the tone) and small positive asynchrony (0-100 ms), whereas we analyzed MV using the coefficient of variation (CV) of the ITI. We found that participants showed predictive tapping under short ISI, irrespective of the tone frequency. Moreover, their MV was unaffected by tone frequency. These findings imply that participants expressed MV in a predictive rather than reactive manner under short, but not long, ISI. Under long ISI, tone frequency had a significant effect on MV such that there was higher MV with the low-frequency than with the high-frequency tone. Thus, low-frequency tones are most suitable for auditory-motor learning in the supra-second range.