Comparing personality traits of healthcare workers with and without long COVID: Cross-sectional study.

Aim: Pathological mechanisms of "long COVID" after recovery from the main symptoms of COVID-19 are unclear. We compared psychological differences between individuals with and without long COVID symptoms after initial COVID-19 infections. Methods: This study includes medical workers with and without history of COVID-19. We assessed the degree of depression, health-related quality of life (HRQOL), the degree of anxiety and fear of COVID-19, and we used an original questionnaire. In the COVID-19 group, we also assessed personality traits and anxiety. The COVID-19 group was subclassified into those with and without long COVID to examine differences in circumstantial and psychological examinations. Results: Of 310 participants (141 men, 169 women, median age: 40 years), 167 had history of COVID-19 (83/84, 37 years) and 143 did not (58 men/85 women, 46 years). In the COVID-19 group, 26 had long COVID (12/14, 32 years) and 141 did not (58/85, 46 years). Fewer participants in the COVID-19 group had had COVID-19 vaccinations. The long COVID group had higher number of symptoms at the time of illness and higher NEO Five Factor Inventory Neuroticism scores than the non-long COVID group. They also had poorer mental health according to HRQOL than those without. Conclusion: Risk factors for long COVID may include the number of symptoms at the time of illness and neurotic tendency on NEO Five Factor Inventory. Participants with long COVID had poorer mental health according to HRQOL. People with long COVID might be especially sensitive to and pessimistic about the symptoms that interfere with their daily lives, resulting in certain cognitive and behavioral patterns. They may benefit from early psychiatric intervention.

Complement component C3 is associated with body composition parameters and sarcopenia in community-dwelling older adults: a cross-sectional study in Japan.

BACKGROUND: Chronic inflammation is a factor in the pathogenesis of sarcopenia, which is characterized by low muscle mass and reduced strength. Complement C3 is important in the management of the immune network system. This study seeks to determine the relationship between serum C3 levels and body composition and sarcopenia-related status in community-dwelling older adults. METHODS: Study participants were 269 older adults living in rural Japan. A bioelectrical impedance analysis device was used to measure body composition parameters including body mass index (BMI), body fat percentage, waist-hip-ratio, and appendicular skeletal muscle mass index (SMI). Muscle function was measured by handgrip strength and 6-m walking speed. The correlation coefficients for C3 level and measurements were calculated using Pearson correlation analysis. Participants were categorized into normal, pre-sarcopenia, dynapenia, or sarcopenia groups. Sarcopenia was defined according to 2019 Asian Working Group for Sarcopenia definition, dynapenia was defined as low muscle function without low muscle mass, and pre-sarcopenia was defined as the presence of low muscle mass only. The C3 threshold score for sarcopenia status was evaluated by receiver operating characteristic curve (ROC) analysis. RESULTS: Significant positive correlations were found between C3 and BMI, body fat percentage, and waist-hip ratio in both sexes, and further positive correlations with SMI were found in women. The relationship with body fat percentage was particularly strong. Body composition measurements (BMI, body fat percentage, and waist- hip ratio) and C3 levels were lowest in the sarcopenia group compared with the others. ROC analysis showed that the significant threshold of C3 for discriminating between the normal and sarcopenia groups was 105 mg/dL. Multiple logistic regression analysis showed that participants with C3 < 105 mg/dL had an odds ratio of 3.27 (95% confidence interval, 1.49-7.18) for sarcopenia adjusted by sex, age and body fat percentage. CONCLUSION: C3 levels are suggested to be related to body composition and pathophysiological functions of sarcopenia. C3 is expected to become a useful biomarker for sarcopenia, for predicting the onset of the disease and for predicting the effectiveness of interventions.

Serum transthyretin level and its relationship with cognitive function in community-dwelling older people: Cross sectional and longitudinal study.

BACKGROUND: Serum transthyretin (TTR) level has suggested association with mild cognitive impairment (MCI) and dementia. To clarify its usefulness as a biomarker of change in cognitive function in older individuals with normal cognitive function (NC) as a phenotype, we investigated the relationship between cognitive scores and TTR levels. We also investigated the involvement of TTR in the transition from NC to MCI. METHODS: Cognitive function was evaluated using Addenbrooke's Cognitive Examination-Revised (ACE-R). A cross-sectional study was conducted in community-dwelling older people (n = 211) with NC, MCI, or dementia according to ACE-R scores. A 32-month longitudinal study was then conducted (n = 29). RESULTS: Mean TTR levels did not differ between the NC, MCI and dementia groups. Linear regression analysis showed a significant relationship in people with NC between TTR and ACE-R (ß = -0.192; p < 0.001). Multiple regression analysis adjusted for stepwise procedure-selected covariates showed that TTR was significantly associated with ACE-R in people with NC (ß = -0.130; p = 0.014). Furthermore, multiple regression analysis showed significant association between TTR level and memory (ß = -0.584; p = 0.002) and with language (ß = -0.743; p = 0.031) in people with NC. In the longitudinal study, mean TTR level at baseline in women with MCI was significantly higher than that in women with NC (p = 0.044). CONCLUSIONS: Serum TTR level is suggested to be associated with cognitive scores in people with NC and to be an indicator of progression from NC to MCI.

Development of Hallux Valgus Classification Using Digital Foot Images with Machine Learning.

Hallux valgus, a frequently seen foot deformity, requires early detection to prevent it from becoming more severe. It is a medical economic problem, so a means of quickly distinguishing it would be helpful. We designed and investigated the accuracy of an early version of a tool for screening hallux valgus using machine learning. The tool would ascertain whether patients had hallux valgus by analyzing pictures of their feet. In this study, 507 images of feet were used for machine learning. Image preprocessing was conducted using the comparatively simple pattern A (rescaling, angle adjustment, and trimming) and slightly more complicated pattern B (same, plus vertical flip, binary formatting, and edge emphasis). This study used the VGG16 convolutional neural network. Pattern B machine learning was more accurate than pattern A. In our early model, Pattern A achieved 0.62 for accuracy, 0.56 for precision, 0.94 for recall, and 0.71 for F1 score. As for Pattern B, the scores were 0.79, 0.77, 0.96, and 0.86, respectively. Machine learning was sufficiently accurate to distinguish foot images between feet with hallux valgus and normal feet. With further refinement, this tool could be used for the easy screening of hallux valgus.

Patient experience of negative pressure wound therapy: A qualitative study.

AIM: This study aimed to clarify the treatment experience of patients undergoing negative pressure wound therapy (NPWT). DESIGN: This study used a qualitative design. METHODS: Seventeen inpatients were semi-structured interviewed about their experiences of treatment with negative pressure wound therapy. RESULTS: Inpatients' answers were categorized into seven themes: pain and discomfort associated with treatment, physical limitations owing to attached device, mental burden owing to the odour and noises of the attached device, social limitations owing to the attached device, advances in medical care and science, device personification and mixed feelings towards medical staff. The patients were able to tolerate the aforementioned limitations while feeling attachment and gratitude towards the device created through advances in medical care and science, and towards medical staff who helped them heal. In the future, we plan to develop an NPWT care guide.

The dipeptide prolyl-hydroxyproline promotes cellular homeostasis and lamellipodia-driven motility via active ß1-integrin in adult tendon cells.

Collagen-derived hydroxyproline (Hyp)-containing peptides have a variety of biological effects on cells. These bioactive collagen peptides are locally generated by the degradation of endogenous collagen in response to injury. However, no comprehensive study has yet explored the functional links between Hyp-containing peptides and cellular behavior. Here, we show that the dipeptide prolyl-4-hydroxyproline (Pro-Hyp) exhibits pronounced effects on mouse tendon cells. Pro-Hyp promotes differentiation/maturation of tendon cells with modulation of lineage-specific factors and induces significant chemotactic activity in vitro. In addition, Pro-Hyp has profound effects on cell proliferation, with significantly upregulated extracellular signal-regulated kinase phosphorylation and extracellular matrix production and increased type I collagen network organization. Using proteomics, we have predicted molecular transport, cellular assembly and organization, and cellular movement as potential linked-network pathways that could be altered in response to Pro-Hyp. Mechanistically, cells treated with Pro-Hyp demonstrate increased directional persistence and significantly increased directed motility and migration velocity. They are accompanied by elongated lamellipodial protrusions with increased levels of active ß1-integrin-containing focal contacts, as well as reorganization of thicker peripheral F-actin fibrils. Pro-Hyp-mediated chemotactic activity is significantly reduced (p < 0.001) in cells treated with the mitogen-activated protein kinase kinase 1/2 inhibitor PD98059 or the α5ß1-integrin antagonist ATN-161. Furthermore, ATN-161 significantly inhibits uptake of Pro-Hyp into adult tenocytes. Thus, our findings document the molecular basis of the functional benefits of the Pro-Hyp dipeptide in cellular behavior. These dynamic properties of collagen-derived Pro-Hyp dipeptide could lead the way to its application in translational medicine.

Broad Recognition of Circulating HIV-1 by HIV-1-Specific Cytotoxic T-Lymphocytes with Strong Ability to Suppress HIV-1 Replication.

HIV-1-specific cytotoxic T-lymphocytes (CTLs) with strong abilities to suppress HIV-1 replication and recognize most circulating HIV-1 strains are candidates for effector T cells for cure treatment and prophylactic AIDS vaccine. Previous studies demonstrated that the existence of CTLs specific for 11 epitopes was significantly associated with good clinical outcomes in Japan, although CTLs specific for one of these epitopes select for escape mutations. However, it remains unknown whether the CTLs specific for the remaining 10 epitopes suppress HIV-1 replication in vitro and recognize circulating HIV-1. Here, we investigated the abilities of these CTLs to suppress HIV-1 replication and to recognize variants in circulating HIV-1. CTL clones specific for 10 epitopes had strong abilities to suppress HIV-1 replication in vitro The ex vivo and in vitro analyses of T-cell responses to variant epitope peptides showed that the T cells specific for 10 epitopes recognized mutant peptides which are detected in 84.1% to 98.8% of the circulating HIV-1 strains found in HIV-1-infected Japanese individuals. In addition, the T cells specific for 5 epitopes well recognized target cells infected with 7 mutant viruses that had been detected in >5% of tested individuals. Taken together, these results suggest that CTLs specific for the 10 epitopes effectively suppress HIV-1 replication and broadly recognize the circulating HIV-1 strains in the HIV-1-infected individuals. This study suggests the use of these T cells in clinical trials.IMPORTANCE In recent T-cell AIDS vaccine trials, the vaccines did not prevent HIV-1 infection, although HIV-1-specific T cells were induced in the vaccinated individuals, suggesting that the T cells have a weak ability to suppress HIV-1 replication and fail to recognize circulating HIV-1. We previously demonstrated that the T-cell responses to 10 epitopes were significantly associated with good clinical outcome. However, there is no direct evidence that these T cells have strong abilities to suppress HIV-1 replication and recognize circulating HIV-1. Here, we demonstrated that the T cells specific for the 10 epitopes had strong abilities to suppress HIV-1 replication in vitro Moreover, the T cells cross-recognized most of the circulating HIV-1 in HIV-1-infected individuals. This study suggests the use of T cells specific for these 10 epitopes in clinical trials of T-cell vaccines as a cure treatment.

Transcription factor scleraxis vitally contributes to progenitor lineage direction in wound healing of adult tendon in mice.

Tendon is a dense connective tissue that transmits high mechanical forces from skeletal muscle to bone. The transcription factor scleraxis (Scx) is a highly specific marker of both precursor and mature tendon cells (tenocytes). Mice lacking scx exhibit a specific and virtually complete loss of tendons during development. However, the functional contribution of Scx to wound healing in adult tendon has not yet been fully characterized. Here, using ScxGFP-tracking and loss-of-function systems, we show in an adult mouse model of Achilles tendon injury that paratenon cells, representing a stem cell antigen-1 (Sca-1)-positive and Scx-negative progenitor subpopulation, display Scx induction, migrate to the wound site, and produce extracellular matrix (ECM) to bridge the defect, whereas resident tenocytes exhibit a delayed response. Scx induction in the progenitors is initiated by transforming growth factor ß (TGF-ß) signaling. scx-deficient mice had migration of Sca-1-positive progenitor cell to the lesion site but impaired ECM assembly to bridge the defect. Mechanistically, scx-null progenitors displayed higher chondrogenic potential with up-regulation of SRY-box 9 (Sox9) coactivator PPAR-γ coactivator-1α (PGC-1α) in vitro, and knock-in analysis revealed that forced expression of full-length scx significantly inhibited Sox9 expression. Accordingly, scx-null wounds formed cartilage-like tissues that developed ectopic ossification. Our findings indicate a critical role of Scx in a progenitor-cell lineage in wound healing of adult mouse tendon. These progenitor cells could represent targets in strategies to facilitate tendon repair. We propose that this lineage-regulatory mechanism in tissue progenitors could apply to a broader set of tissues or biological systems in the body.

HLA Class I-Mediated HIV-1 Control in Vietnamese Infected with HIV-1 Subtype A/E.

HIV-1-specific cytotoxic T cells (CTLs) play an important role in the control of HIV-1 subtype B or C infection. However, the role of CTLs in HIV-1 subtype A/E infection still remains unclear. Here we investigated the association of HLA class I alleles with clinical outcomes in treatment-naive Vietnamese infected with subtype A/E virus. We found that HLA-C*12:02 was significantly associated with lower plasma viral loads (pVL) and higher CD4 counts and that the HLA-A*29:01-B*07:05-C*15:05 haplotype was significantly associated with higher pVL and lower CD4 counts than those for individuals without these respective genotypes. Nine Pol and three Nef mutations were associated with at least one HLA allele in the HLA-A*29:01-B*07:05-C*15:05 haplotype, with a strong negative correlation between the number of HLA-associated Pol mutations and CD4 count as well as a positive correlation with pVL for individuals with these HLA alleles. The results suggest that the accumulation of mutations selected by CTLs restricted by these HLA alleles affects HIV control.IMPORTANCE Most previous studies on HLA association with disease progression after HIV-1 infection have been performed on cohorts infected with HIV-1 subtypes B and C, whereas few such population-based studies have been reported for cohorts infected with the Asian subtype A/E virus. In this study, we analyzed the association of HLA class I alleles with clinical outcomes for 536 HIV-1 subtype A/E-infected Vietnamese individuals. We found that HLA-C*12:02 is protective, while the HLA haplotype HLA-A*29:01-B*07:05-C*15:05 is deleterious. The individuals with HIV-1 mutations associated with at least one of the HLA alleles in the deleterious HLA haplotype had higher plasma viral loads and lower CD4 counts than those of individuals without the mutations, suggesting that viral adaptation and escape from HLA-mediated immune control occurred. The present study identifies a protective allele and a deleterious haplotype for HIV-1 subtype A/E infection which are different from those identified for cohorts infected with HIV-1 subtypes B and C.

Evaluation of the Predictive Validity of Thermography in Identifying Extravasation With Intravenous Chemotherapy Infusions.

Early detection of extravasation is important, but conventional methods of detection lack objectivity and reliability. This study evaluated the predictive validity of thermography for identifying extravasation during intravenous antineoplastic therapy. Of 257 patients who received chemotherapy through peripheral veins, extravasation was identified in 26. Thermography was performed every 15 to 30 minutes during the infusions. Sensitivity, specificity, positive predictive value, and negative predictive value using thermography were 84.6%, 94.8%, 64.7%, and 98.2%, respectively. This study showed that thermography offers an accurate prediction of extravasation.

Accumulation of Pol Mutations Selected by HLA-B*52:01-C*12:02 Protective Haplotype-Restricted Cytotoxic T Lymphocytes Causes Low Plasma Viral Load Due to Low Viral Fitness of Mutant Viruses.

HLA-B*52:01-C*12:02, which is the most abundant haplotype in Japan, has a protective effect on disease progression in HIV-1-infected Japanese individuals, whereas HLA-B*57 and -B*27 protective alleles are very rare in Japan. A previous study on HLA-associated polymorphisms demonstrated that the number of HLA-B*52:01-associated mutations at four Pol positions was inversely correlated with plasma viral load (pVL) in HLA-B*52:01-negative individuals, suggesting that the transmission of HIV-1 with these mutations could modulate the pVL in the population. However, it remains unknown whether these mutations were selected by HLA-B*52:01-restricted CTLs and also reduced viral fitness. In this study, we identified two HLA-B*52:01-restricted and one HLA-C*12:02-restricted novel cytotoxic T-lymphocyte (CTL) epitopes in Pol. Analysis using CTLs specific for these three epitopes demonstrated that these CTLs failed to recognize mutant epitopes or more weakly recognized cells infected with mutant viruses than wild-type virus, supporting the idea that these mutations were selected by the HLA-B*52:01- or HLA-C*12:02-restricted T cells. We further showed that these mutations reduced viral fitness, although the effect of each mutation was weak. The present study demonstrated that the accumulation of these Pol mutations selected by HLA-B*52:01- or HLA-C*12:02-restricted CTLs impaired viral replication capacity and thus reduced the pVL. The fitness cost imposed by the mutations partially accounted for the effect of the HLA-B*52:01-C*12:02 haplotype on clinical outcome, together with the effect of HLA-B*52:01-restricted CTLs on viral replication, which had been previously demonstrated. IMPORTANCE: Numerous population-based studies identified HLA-associated HIV-1 mutations to predict HIV-1 escape mutations from cytotoxic T lymphocytes (CTLs). However, the majority of these HLA-associated mutations have not been identified as CTL escape mutations. Our previous population-based study showed that five HLA-B*52:01-associated mutations at four Pol positions were inversely correlated with the plasma viral load in HLA-B*52:01-negative Japanese individuals. In the present study, we demonstrated that these mutations were indeed selected by CTLs specific for novel B*52:01- and C*12:02-restricted epitopes and that the accumulation of these mutations reduced the viral fitness in vitro This study elucidated the mechanism by which the accumulation of these CTL escape mutations contributed to the protective effect of the HLA-B*52:01-HLA-C*12:02 haplotype on disease progression in HIV-1-infected Japanese individuals.

Macrophage-secreted granulin supports pancreatic cancer metastasis by inducing liver fibrosis.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating metastatic disease for which better therapies are urgently needed. Macrophages enhance metastasis in many cancer types; however, the role of macrophages in PDAC liver metastasis remains poorly understood. Here we found that PDAC liver metastasis critically depends on the early recruitment of granulin-secreting inflammatory monocytes to the liver. Mechanistically, we demonstrate that granulin secretion by metastasis-associated macrophages (MAMs) activates resident hepatic stellate cells (hStCs) into myofibroblasts that secrete periostin, resulting in a fibrotic microenvironment that sustains metastatic tumour growth. Disruption of MAM recruitment or genetic depletion of granulin reduced hStC activation and liver metastasis. Interestingly, we found that circulating monocytes and hepatic MAMs in PDAC patients express high levels of granulin. These findings suggest that recruitment of granulin-expressing inflammatory monocytes plays a key role in PDAC metastasis and may serve as a potential therapeutic target for PDAC liver metastasis.

[The relationship between perceived personality and Ieading/following roles in university students' close friendships, using Gitaigo personality scale].

Based on the recently developed Gitaigo personality scale (Komatsu, Sakai, Nishioka, & Mukoyama, 2012), we investigated the relationship between perceived personality and leading/following roles in close friend dyads. Primary participants rated their own and one of their close friend's personality with Gitaigo personality scale. They also described who takes the role of leader in the relationship with the friend they rated. When one in the pair is reported as leader, the other is considered as follower. Subsidiary participants who were cited as close friends rated their own personality. Our analysis of the 215 pairs showed that the participants taking the role of follower were rated higher in the traits of Cowardliness and Mildness by the primary participants. Regarding Mildness, this tendency was also clear in subsidiary participants' self-ratings. Primary participants rated the Preciseness and Candidness of their friends lower if their friend was considered a follower. Gitaigo personality scale describes the perceived personality well, at least for several traits.

Molecular Mechanism Responsible for Fibronectin-controlled Alterations in Matrix Stiffness in Advanced Chronic Liver Fibrogenesis.

Fibrosis is characterized by extracellular matrix (ECM) remodeling and stiffening. However, the functional contribution of tissue stiffening to noncancer pathogenesis remains largely unknown. Fibronectin (Fn) is an ECM glycoprotein substantially expressed during tissue repair. Here we show in advanced chronic liver fibrogenesis using a mouse model lacking Fn that, unexpectedly, Fn-null livers lead to more extensive liver cirrhosis, which is accompanied by increased liver matrix stiffness and deteriorated hepatic functions. Furthermore, Fn-null livers exhibit more myofibroblast phenotypes and accumulate highly disorganized/diffuse collagenous ECM networks composed of thinner and significantly increased number of collagen fibrils during advanced chronic liver damage. Mechanistically, mutant livers show elevated local TGF-ß activity and lysyl oxidase expressions. A significant amount of active lysyl oxidase is released in Fn-null hepatic stellate cells in response to TGF-ß1 through canonical and noncanonical Smad such as PI3 kinase-mediated pathways. TGF-ß1-induced collagen fibril stiffness in Fn-null hepatic stellate cells is significantly higher compared with wild-type cells. Inhibition of lysyl oxidase significantly reduces collagen fibril stiffness, and treatment of Fn recovers collagen fibril stiffness to wild-type levels. Thus, our findings indicate an indispensable role for Fn in chronic liver fibrosis/cirrhosis in negatively regulating TGF-ß bioavailability, which in turn modulates ECM remodeling and stiffening and consequently preserves adult organ functions. Furthermore, this regulatory mechanism by Fn could be translated for a potential therapeutic target in a broader variety of chronic fibrotic diseases.

A strong association of human leukocyte antigen-associated Pol and Gag mutations with clinical parameters in HIV-1 subtype A/E infection.

OBJECTIVES: Identification of human leukocyte antigen-associated HIV-1 polymorphisms (HLA-APs) in different global populations furthers our understanding of HIV-1 pathogenesis and may help identify candidate immunogens for HIV vaccines targeted to these populations. Although numerous population-based studies identifying HLA-APs have been conducted in HIV-1 subtype B- and subtype C-infected cohorts, few have focused on subtype A/E. DESIGN: We investigated HLA-APs in a cohort of chronically HIV-1 subtype A/E-infected Vietnamese individuals. METHODS: HLA-APs in HIV-1 Gag, Pol, and Nef regions from 388 treatment-naive individuals chronically infected with HIV-1 subtype A/E were analyzed using phylogenetically informed approaches. RESULTS: A total of 303 HLA-APs were identified. HLA-APs occurring at six positions in Gag and six positions in Pol were significantly associated with higher plasma viral load (pVL), whereas HLA-APs occurring at two positions in Gag and 13 positions in Pol were significantly associated with lower CD4 T-cell counts. Furthermore, the proportion of Pol codons harboring an HLA-AP specific to the host's HLA correlated positively with HIV-1 pVL (R = 0.22; P < 0.0001) and inversely with CD4 T-cell counts (R = -0.32; P < 0.0001). Similarly, the proportion of HLA-associated Gag codons harboring host-specific HLA-AP correlated inversely with CD4 T-cell counts (R = -0.13; P = 0.01). CONCLUSION: These significant associations between HIV-1 amino acids adapted to Vietnamese HLA alleles and higher pVL and lower CD4 T-cell counts suggests that accumulation of cytotoxic T cells escape mutations may influence clinical outcomes in HIV-1 subtype A/E-infected Vietnamese individuals.

Lack of a significant impact of Gag-Protease-mediated HIV-1 replication capacity on clinical parameters in treatment-naive Japanese individuals.

BACKGROUND: HLA class I-associated escape mutations in HIV-1 Gag can reduce viral replication, suggesting that associated fitness costs could impact HIV-1 disease progression. Previous studies in North American and African cohorts have reported reduced Gag-Protease mediated viral replication capacity (Gag-Pro RC) in individuals expressing protective HLA class I alleles including HLA-B*57:01, B*27:05, and B*81:01. These studies also reported significant positive associations between Gag-Pro RCs and plasma viral load (pVL). However, these HLA alleles are virtually absent in Japan, and the importance of Gag as an immune target is not clearly defined in this population. RESULTS: We generated chimeric NL4-3 viruses carrying patient-derived Gag-Protease from 306 treatment-naive Japanese individuals chronically infected with HIV-1 subtype B. We analyzed associations between Gag-Pro RC and clinical markers of HIV-1 infection and host HLA expression. We observed no significant correlation between Gag-Pro RC and pVL in Japan in the overall cohort. However, upon exclusion of individuals expressing Japanese protective alleles HLA-B*52:01 and B*67:01, Gag-Pro RC correlated positively with pVL and negatively with CD4 T-cell count. Our results thus contrast with studies from other global cohorts reporting significantly lower Gag-Pro RC among persons expressing protective HLA alleles, and positive relationships between Gag-Pro RC and pVL in the overall study populations. We also identified five amino acids in Gag-Protease significantly associated with Gag-Pro RC, whose effects on RC were confirmed by site-directed mutagenesis. However, of the four mutations that decreased Gag-Pro RC, none were associated with reductions in pVL in Japan though two were associated with lower pVL in North America. CONCLUSIONS: These data indicate that Gag fitness does not affect clinical outcomes in subjects with protective HLA class I alleles as well as the whole Japanese population. Moreover, the impact of Gag fitness costs on HIV-1 clinical parameters in chronic infection is likely low in Japan compared to other global populations.

A thyroid hormone receptor/KLF9 axis in human hepatocytes and pluripotent stem cells.

Biological processes require close cooperation of multiple transcription factors that integrate different signals. Thyroid hormone receptors (TRs) induce Krüppel-like factor 9 (KLF9) to regulate neurogenesis. Here, we show that triiodothyronine (T3) also works through TR to induce KLF9 in HepG2 liver cells, mouse liver, and mouse and human primary hepatocytes and sought to understand TR/KLF9 network function in the hepatocyte lineage and stem cells. Knockdown experiments reveal that KLF9 regulates hundreds of HepG2 target genes and modulates T3 response. Together, T3 and KLF9 target genes influence pathways implicated in stem cell self-renewal and differentiation, including Notch signaling, and we verify that T3 and KLF9 cooperate to regulate key Notch pathway genes and work independently to regulate others. T3 also induces KLF9 in human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSC) and this effect persists during differentiation to definitive endoderm and hiPSC-derived hepatocytes. Microarray analysis reveals that T3 regulates hundreds of hESC and hiPSC target genes that cluster into many of the same pathways implicated in TR and KLF9 regulation in HepG2 cells. KLF9 knockdown confirms that TR and KLF9 cooperate to regulate Notch pathway genes in hESC and hiPSC, albeit in a partly cell-specific manner. Broader analysis of T3 responsive hESC/hiPSC genes suggests that TRs regulate multiple early steps in ESC differentiation. We propose that TRs cooperate with KLF9 to regulate hepatocyte proliferation and differentiation and early stages of organogenesis and that TRs exert widespread and important influences on ESC biology.