Miracle-dz/UniFAR-FTUs huggingface dataset:
The C Terminus of the Herpes Simplex Virus UL25 Protein Is Required for Release of Viral Genomes from Capsids Bound to Nuclear Pores

ABSTRACT The herpes simplex virus (HSV) capsid is released into the cytoplasm after fusion of viral and host membranes, whereupon dynein-dependent trafficking along microtubules targets it to the nuclear envelope. Binding of the capsid to the nuclear pore complex (NPC) is mediated by the capsid protein pUL25 and the capsid-tethered tegument protein pUL36. Temperature-sensitive mutants in both pUL25 and pUL36 dock at the NPC but fail to release DNA. The uncoating reaction has been difficult to study due to the rapid release of the genome once the capsid interacts with the nuclear pore. In this study, we describe the isolation and characterization of a truncation mutant of pUL25. Live-cell imaging and immunofluorescence studies demonstrated that the mutant was not impaired in penetration of the host cell or in trafficking of the capsid to the nuclear membrane. However, expression of viral proteins was absent or significantly delayed in cells infected with the pUL25 mutant virus. Transmission electron microscopy revealed capsids accumulated at nuclear pores that retained the viral genome for at least 4 h postinfection. In addition, cryoelectron microscopy (cryo-EM) reconstructions of virion capsids did not detect any obvious differences in the location or structural organization for the pUL25 or pUL36 proteins on the pUL25 mutant capsids. Further, in contrast to wild-type virus, the antiviral response mediated by the viral DNA-sensing cyclic guanine adenine synthase (cGAS) was severely compromised for the pUL25 mutant. These results demonstrate that the pUL25 capsid protein has a critical role in releasing viral DNA from NPC-bound capsids. IMPORTANCE Herpes simplex virus 1 (HSV-1) is the causative agent of several pathologies ranging in severity from the common cold sore to life-threatening encephalitic infection. Early steps in infection include release of the capsid into the cytoplasm, docking of the capsid at a nuclear pore, and release of the viral genome into the nucleus. A key knowledge gap is how the capsid engages the NPC and what triggers release of the viral genome into the nucleus. Here we show that the C-terminal region of the HSV-1 pUL25 protein is required for releasing the viral genome from capsids docked at nuclear pores. The significance of our research is in identifying pUL25 as a key viral factor for genome uncoating. pUL25 is found at each of the capsid vertices as part of the capsid vertex-specific component and implicates the importance of this complex for NPC binding and genome release.
Demographic and lifestyle characteristics associated with non-willingness to participate in health promotion programmes among adults of a lower socioeconomic status in Singapore

Introduction/Objective Lower socioeconomic groups have been found to have poorer health outcomes and engage in fewer health promoting behaviours. Understanding the reasons behind adverse lifestyle habits and non-willingness to participate in health promotion programmes among lower socioeconomic groups will enable administrators to modify the programmes and increase participation in this population. This study aimed to determine reasons for non-exercise, smoking and non-willingness to participate, and characteristics associated with non-willingness to participate in health promotion programmes among residents in Singapore. Method A cross-sectional survey was conducted on a purposive sample of residents living in four housing developments of one- and two-room households in Singapore from June to October 2009. The patterns of exercise and smoking, receptiveness towards health promotion programmes and the reasons for non-willingness to participate were elicited. Chi-square tests and logistic regression analysis were performed to identify differences between groups. Results Seven hundred and seventy-eight responses were analysed. Only 36.1% of respondents were willing to participate in at least one health promotion programme (health screening, talk or workshop). Older respondents aged 45–64 years and more than 65 years were less likely to participate than their younger counterparts (18–44 years). Malays were more likely than Chinese to participate, and respondents who do not exercise were less likely to participate than respondents who exercise (regularly/occasionally). Reasons for non-willingness to participate were ‘not interested’ and ‘no time’. Conclusion Health promotion messages should adapt to the needs and situation of the disadvantaged, to increase participation.
Genome Sequence of Herpes Simplex Virus 1 Strain KOS

ABSTRACT Herpes simplex virus type 1 (HSV-1) strain KOS has been extensively used in many studies to examine HSV-1 replication, gene expression, and pathogenesis. Notably, strain KOS is known to be less pathogenic than the first sequenced genome of HSV-1, strain 17. To understand the genotypic differences between KOS and other phenotypically distinct strains of HSV-1, we sequenced the viral genome of strain KOS. When comparing strain KOS to strain 17, there are at least 1,024 small nucleotide polymorphisms (SNPs) and 172 insertions/deletions (indels). The polymorphisms observed in the KOS genome will likely provide insights into the genes, their protein products, and the cis elements that regulate the biology of this HSV-1 strain.
Isolation and TLC Densitometric Quantification of Lysergol from the Seeds of Ipomoea muricata (Linn.) Jacq.

Seeds of Ipomoea muricata, well known in Ayurveda for its purgative action, contains mainly indole alkaloids. Lysergol (major alkaloid) exhibits hypotensive, psychotropic, and uterus and intestine-stimulating properties. TLC fingerprint profile of I. muricata seeds was developed using chloroform : methanol (95 : 5 v/v) as the mobile phase. Plate was visualized under UV 254 nm and UV 366 nm and after derivatization with Van Urk reagent. Lysergol resolved at . Further, TLC-densitometric method was developed and validated for quantification of Lysergol avoiding derivatization step. Ethyl acetate : methanol (7 : 3 v/v) was used as the mobile phase. Linear regression analysis data for the calibration curve showed a good linear relationship () in the concentration range from 20 ng to 140 ng, with respect to the peak area. The developed method was precise with RSD for intraday (range from 1.20 to 1.89) and interday (range from 1.39 to 1.92) for 60, 80, and 100 ng/spot of Lysergol. The instrumental precision was 0.67 (% RSD). The limit of detection and limit of quantification for Lysergol were 12 ng and 40 ng, respectively. The average percentage recovery was 99.68. The amount of Lysergol was found to be 0.23% w/w. To the best of our knowledge, this is the first report for the quantification of Lysergol from I. muricata seeds without derivatization.
Constrained optimization for audio-to-visual conversion

We have developed a new audio-to-visual conversion algorithm that uses a constrained optimization approach to take advantage of dynamics of mouth movements. Based on facial muscle analysis, the dynamics of mouth movements is modeled, and constraints are obtained from it. The obtained constraints are used to estimate visual parameters from speech in a framework of hidden Markov model (HMM)-based visual parameter estimation. To solve the constrained optimization problem, the Lagrangian approach is used to transform the constrained problem into an unconstrained problem in our implementation. The proposed method is tested on various noisy environments to show its robustness and correctness. Our proposed algorithm is favorably compared with the mixture-based HMM method, which also uses audio-visual HMMs and finds optimal estimates based on a joint audio-visual probability distribution. Our proposed algorithm can estimate optimal visual parameters while satisfying the constraints and avoiding performance degradation in noisy environments.
Brd4 Regulation of Papillomavirus Protein E2 Stability

ABSTRACT The papillomavirus (PV) E2 protein is an important regulator of the viral life cycle. It has diverse roles in viral transcription, DNA replication, and genome maintenance. Our laboratory has previously identified the cellular bromodomain protein Brd4 as a key interacting partner of E2. Brd4 mediates the transcriptional activation function of E2 and plays an important role in viral genome maintenance in dividing cells. E2 interacts with the C-terminal domain (CTD) of Brd4, and the CTD functions in a dominant-negative manner through binding E2 and interfering with E2's interaction with the full-length Brd4 protein. Previous studies have shown that PV E2 proteins are short lived; however, the mechanisms regulating their stability and degradation have not yet been well established. In this study, we explored the role of Brd4 in the regulation of bovine PV 1 (BPV1) and human PV 16 (HPV16) E2 stability. Expression of the Brd4 CTD dramatically increases E2 levels. Both BPV1 E2 and HPV16 E2 are regulated by ubiquitylation, and Brd4 CTD expression blocks this ubiquitylation, thus stabilizing the E2 protein. Furthermore, we have identified the cullin-based E3 ligases and specifically cullin-3 as potential components of the ubiquitylation machinery that targets both BPV1 and HPV16 E2 for ubiquitylation. Expression of the Brd4 CTD blocks the interaction between E2 and the cullin-3 complex. In addition to Brd4's role in mediating E2 transcription and genome tethering activities, these data suggest a potential role for Brd4 in regulating E2 stability and protein levels within PV-infected cells.
Competitive Fitness of Oseltamivir-Sensitive and -Resistant Highly Pathogenic H5N1 Influenza Viruses in a Ferret Model

ABSTRACT The fitness of oseltamivir-resistant highly pathogenic H5N1 influenza viruses has important clinical implications. We generated recombinant human A/Vietnam/1203/04 (VN; clade 1) and A/Turkey/15/06 (TK; clade 2.2) influenza viruses containing the H274Y neuraminidase (NA) mutation, which confers resistance to NA inhibitors, and compared the fitness levels of the wild-type (WT) and resistant virus pairs in ferrets. The VN-H274Y and VN-WT viruses replicated to similar titers in the upper respiratory tract (URT) and caused comparable disease signs, and none of the animals survived. On days 1 to 3 postinoculation, disease signs caused by oseltamivir-resistant TK-H274Y virus were milder than those caused by TK-WT virus, and all animals survived. We then studied fitness by using a novel approach. We coinoculated ferrets with different ratios of oseltamivir-resistant and -sensitive H5N1 viruses and measured the proportion of clones in day-6 nasal washes that contained the H274Y NA mutation. Although the proportion of VN-H274Y clones increased consistently, that of TK-H274Y virus decreased. Mutations within NA catalytic (R292K) and framework (E119A/K, I222L, H274L, and N294S) sites or near the NA enzyme active site (V116I, I117T/V, Q136H, K150N, and A250T) emerged spontaneously (without drug pressure) in both pairs of viruses. The NA substitutions I254V and E276A could exert a compensatory effect on the fitness of VN-H274Y and TK-H274Y viruses. NA enzymatic function was reduced in both drug-resistant H5N1 viruses. These results show that the H274Y NA mutation affects the fitness of two H5N1 influenza viruses differently. Our novel method of assessing viral fitness accounts for both virus-host interactions and virus-virus interactions within the host.
Atypical hyperplastic lesions of the female breast. A long‐term follow‐up study

A total of 10,542 breast biopsy specimens obtained between 1950 and 1968 were studied. Examples of atypical “ductal” (ADH) and atypical lobular hyperplasia (ALH), defined as having only some features of carcinoma in situ (CIS), were diagnosed in 3.6% of these specimens. In the same series, CIS was diagnosed in 1.7% of biopsy specimens excluding those with invasive cancer. The subsequent risk of invasive breast carcinoma after ALH or ADH was 4–5 times that of the general population. Follow‐up was 90% successful and extended 17 years after biopsy. History of breast cancer in a mother, sister, or daughter doubled the risk of subsequent invasive carcinoma development (to 8 times for ALH and 10 times for ADH). The authors conclude that among the epithelial hyperplastic lesions of the human breast, a minority may be recognized by their resemblance to CIS which have a clinically significant elevation of subsequent breast cancer risk. This risk is one‐half that of CIS.
Nonorthogonal Joint Diagonalization Free of Degenerate Solution

The problem of approximate joint diagonalization of a set of matrices is instrumental in numerous statistical signal processing applications. For nonorthogonal joint diagonalization based on the weighted least-squares (WLS) criterion, the trivial (zero) solution can simply be avoided by adopting some constraint on the diagonalizing matrix or penalty terms. However, the resultant algorithms may converge to some undesired degenerate solutions (nonzero but singular or ill-conditioned solutions). This paper discusses and analyzes the problem of degenerate solutions in detail. To solve this problem, a novel nonleast-squares criterion for approximate nonorthogonal joint diagonalization is proposed and an efficient algorithm, called fast approximate joint diagonalization (FAJD), is developed. As compared with the existing nonorthogonal diagonalization algorithms, the new algorithm can not only avoid the trivial solution but also any degenerate solutions. Theoretical analysis shows that the FAJD algorithm has some advantages over the existing nonorthogonal diagonalization algorithms. Simulation results are presented to demonstrate the efficiency of this paper's algorithm
Seasonal food consumption patterns and dietary diversity of rural preschool Ghanaian and Malawian children

Food intakes of rural Malawian (29F. 36M; 62 ± 10 mo) and Ghanaian (83F, 65M; 59 ± 10 mo) children were estimated at two seasons using 3‐day weighed records. Food patterns, dietary diversity, based on the number, and frequency of foods consumed, and major sources of energy and selected nutrients were examined. The total, and average number of food items consumed per day were lower in Malawi (62, 6.4 ± 1.4 per day) than in Ghana (70 ‐ 76. 7.5 ± 1.3 ‐ 8.0 ± 1.2 per day). More Malawian than Ghanaian children (25 and 46% versus 12 and 27%, depending on season) consumed 6 food items or less per day. Major energy sources were cereals (51–69%) in Malawi, and cereals (24–41%), and roots (24–37%) in Ghana; animal products contributed 3–7% of the energy. Dietary diversity was associated with intakes of energy (per kg BW) (r = 0.33–0.41; p < 0.02) in Malawi, the consumption of prestigious foods and snacks in both countries, and with purchased meals in Ghana. Hence, increased consumption of nutrient dense purchased m.
Scars of disengagement: perspectives on community leadership and youth engagement in rural South Africa

Given the emerging global youth disengagement epidemic, anticipated population growth, and the threat of continued rural–urban migration among young adults, recent research has focused on community leadership practice and the factors that influence youth engagement at the local level. Studying these practices and factors can elicit interventions that can improve youth engagement and youth health. This study engaged South African rural community leaders in interviews to collect perceptions and experiences on community leadership and factors that influence youth engagement and their health behaviors. Content analysis was used to analyze the data. Emergent themes are categorized into four domains: conceptualizations of leadership, current youth behaviors, barriers to youth engagement, and youth leadership opportunities and potential solutions. Findings demonstrate a clear grasp of the concept of community leadership among community leaders, and an awareness of the complex interplay of social, economic and environmental factors on youth disengagement and the potential interventions to promote more youth participation.
Efficient Design of High-Complexity Cosine Modulated Filter Banks Using $2 M$th Band Conditions

This paper presents several new properties of biorthogonal cosine modulated filter banks (CMFBs) and efficient algorithms for designing CMFBs with a very large number of subbands and very long filters. For a biorthogonal CMFB, we find the periodicity and symmetry of its overall transfer function and aliasing transfer functions which can be efficiently computed based on a decimated uniform discrete Fourier transform (DFT) analysis filter bank. By exploiting gradient information and 2M th band conditions, efficient algorithms are proposed for designing both orthogonal and biorthogonal CMFBs. In addition, an efficient matrix inversion algorithm with O(N 2 ) complexity is also presented. Several numerical examples and comparisons with many other existing methods are included to demonstrate the design performance and efficiency of the algorithms.
Virion-Associated Vpr of Human Immunodeficiency Virus Type 1 Triggers Activation of Apoptotic Events and Enhances Fas-Induced Apoptosis in Human T Cells

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) Vpr protein exists in three different forms: soluble, intracellular, and virion associated. Previous studies showed that virion-associated Vpr induces apoptosis in activated peripheral blood mononuclear cells (PBMCs) and Jurkat T cells, but these studies were conducted in the presence of other de novo-expressed HIV proteins that may have had additive proapoptotic effects. In this report, we show that virion-associated Vpr triggers apoptosis through caspases 3/7 and 9 in human T cells independently of other HIV de novo-expressed proteins. In contrast to a previous study, we also detected the activation of caspase 8, the initiator caspase of the death receptor pathway. However, activation of all caspases by virion-associated Vpr was independent of the Fas death receptor pathway. Further analyses showed that virion-associated Vpr enhanced caspase activation in Fas-mediated apoptosis in Jurkat T cells and human activated PBMCs. Thus, our results indicate for the first time that viral particles that contain virion-associated Vpr can cause apoptosis in the absence of other de novo-expressed viral factors and can act in synergy with the Fas receptor pathway, thereby enhancing the apoptotic process in T cells. These findings suggest that virion-associated Vpr can contribute to the depletion of CD4+ lymphocytes either directly or by enhancing Fas-mediated apoptosis during acute HIV-1 infection and in AIDS.
Cytokine/Chemokine Responses in Activated CD4+ and CD8+ T Cells Isolated from Peripheral Blood, Bone Marrow, and Axillary Lymph Nodes during Acute Simian Immunodeficiency Virus Infection

ABSTRACT Understanding the cytokine/chemokine networks in CD4+ and CD8+ T cells during the acute phase of infection is crucial to design therapies for the control of early human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) replication. Here, we measured early changes in CD4+ and CD8+ T cells in the peripheral blood (PB), bone marrow (BM), and axillary lymph node (ALN) tissue of rhesus macaques infected with SIVMAC251. At 21 days after infection, all tissues showed a statistically significant loss of CD4+ T cells along with immune activation of CD8+ T cells in PB and ALN tissue. Twenty-eight different cytokines/chemokines were quantified in either anti-CD3/28 antibody- or staphylococcal enterotoxin B-stimulated single-positive CD4+ and CD8+ T cells. PB CD4+ T cells produced predominantly interleukin-2 (IL-2), whereas CD4+ and CD8+ T-cell subsets in tissues produced β-chemokines both before and 21 days after SIV infection. Tissues generally exhibited massive upregulation of many cytokines/chemokines following infection, possibly in an attempt to mitigate the loss of CD4+ T cells. There was no evidence of a T-helper 1 (TH1)-to-TH2 shift in CD4+ T cells or a T-cytotoxic 1 (TC1)-to-TC2 cytokine shift in CD8+ T cells in PB, BM, and ALN T-cell subsets during the acute phase of SIV infection. Despite the upregulation of several important effector cytokines/chemokines (IL-2, IL-12, IL-17, gamma interferon, granulocyte-macrophage colony-stimulating factor) by CD4+ and CD8+ T cells, upregulation of β-chemokines (CCL2 and CCL22), basic fibroblast growth factor (FGF-basic), hepatocyte growth factor (HGF), and migration inhibition factor (MIF) may provide a poor prognosis either by inducing increased virus replication or by other unknown mechanisms. Therefore, drugs targeting β-chemokines (CCL2 and CCL22), FGF-basic, HGF, or MIF might be important for developing effective vaccines and therapeutics against HIV. IMPORTANCE Human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) infection results in early depletion of CD4+ T cells and dysregulation of protective immune responses. Therefore, understanding the cytokine/chemokine networks in CD4+ and CD8+ T cells in different tissues during the acute phase of infection is crucial to the design of therapies for the control of early viral replication. Here, we measured early changes in CD4+ and CD8+ T cells in peripheral blood (PB), bone marrow (BM), and axillary lymph node (ALN) tissue of rhesus macaques infected with SIVMAC251. There was no evidence of a T-helper 1 (TH1)-to-TH2 shift in CD4+ T cells or a T-cytotoxic 1 (TC1)-to-TC2 cytokine shift in CD8+ T cells in PB, BM, and ALN T-cell subsets during the acute phase of SIV infection. Despite the upregulation of several important effector cytokines/chemokines by CD4+ and CD8+ T cells, upregulation of β-chemokines, fibroblast growth factor-basic, hepatocyte growth factor, and migration inhibition factor may provide a poor prognosis.
Review: Therapeutic opportunities in noncutaneous melanoma

Recent evidence suggests that the biology of noncutaneous melanoma differs significantly from cutaneous melanoma and may provide therapeutic opportunity. The most frequent sites of origin of noncutaneous melanoma are the eye and mucosal surfaces. Although noncutaneous melanomas are an uncommon group of cancers (representing less than 10% of all melanomas) a greater understanding of their genetic and molecular abnormalites is being translated into novel treatment strategies. These developments are important because there is currently no effective systemic therapy for noncutaneous melanoma. Significant attention has been focused on the role of c-kit (KIT, CD117), a transmembrane receptor with tyrosine kinase activity. In vitro and ex vivo evidence suggests that c-kit is frequently expressed/over expressed/mutated in noncutaneous melanoma. Anti-tumour effects with c-kit inhibitors are seen in pre-clinical models. A variety of multitargeted kinase inhibitors which have activity against c-kit are currently in early phase clinical trials in metastatic ocular, mucosal and acral melanoma. The few case reports of significant clinical activity with targeted therapies provides hope that greater understanding of the biology of noncutaneous melanoma can be translated into effective treatment.