Miracle-dz/UniFAR-FTUs huggingface dataset:
Latest developments and future directions in dengue vaccines

Dengue is a mosquito-borne disease which is currently an expanding global health problem. The disease is caused by four closely related viruses, the dengue virus. There are no specific dengue therapeutics and prevention is currently limited to vector control measures. Development of an effective tetravalent dengue vaccine would therefore represent a major advance in the control of the disease and is considered a high public health priority. While a licensed dengue vaccine is not yet available, the scope and intensity of dengue vaccine development has increased dramatically in the last decade. The uniqueness of the dengue viruses and the spectrum of disease resulting from infection have made dengue vaccine development difficult. Several vaccine candidates are currently being evaluated in clinical studies. The candidate currently at the most advanced clinical development stage, a live-attenuated tetravalent vaccine based on chimeric yellow fever dengue virus, has progressed to phase III efficacy studies. Several other live-attenuated vaccines, as well as subunit, DNA and purified inactivated vaccine candidates, are at earlier stages of clinical development. Additional technological approaches, such as virus-vectored and virus-like particle-based vaccines, are under evaluation in preclinical studies.
SIRT3 Functions in the Nucleus in the Control of Stress-Related Gene Expression

ABSTRACT SIRT3 is a member of the Sir2 family of NAD+-dependent protein deacetylases that promotes longevity in many organisms. The processed short form of SIRT3 is a well-established mitochondrial protein whose deacetylase activity regulates various metabolic processes. However, the presence of full-length (FL) SIRT3 in the nucleus and its functional importance remain controversial. Our previous studies demonstrated that nuclear FL SIRT3 functions as a histone deacetylase and is transcriptionally repressive when artificially recruited to a reporter gene. Here, we report that nuclear FL SIRT3 is subjected to rapid degradation under conditions of cellular stress, including oxidative stress and UV irradiation, whereas the mitochondrial processed form is unaffected. FL SIRT3 degradation is mediated by the ubiquitin-proteasome pathway, at least partially through the ubiquitin protein ligase (E3) activity of SKP2. Finally, we show by chromatin immunoprecipitation that some target genes of nuclear SIRT3 are derepressed upon degradation of SIRT3 caused by stress stimuli. Thus, SIRT3 exhibits a previously unappreciated role in the nucleus, modulating the expression of some stress-related and nuclear-encoded mitochondrial genes.
Role of Deubiquitinating Enzymes in DNA Repair

ABSTRACT Both proteolytic and nonproteolytic functions of ubiquitination are essential regulatory mechanisms for promoting DNA repair and the DNA damage response in mammalian cells. Deubiquitinating enzymes (DUBs) have emerged as key players in the maintenance of genome stability. In this minireview, we discuss the recent findings on human DUBs that participate in genome maintenance, with a focus on the role of DUBs in the modulation of DNA repair and DNA damage signaling.
External Fixation About the Knee in High-energy War Injuries

External fixation for the treatment of musculoskeletal injuries in the current military conflicts has emerged as a vital part of the treatment of high-energy war injuries, including those involving the knee. Spanning fixators are a simple, safe, and rapid way to obtain stability and alignment about the knee during the transport and evacuation phases of the care of wounded military personnel. This provides a much needed damage control technique for the overall resuscitation and comfort of the injured military personnel as well helping to stabilize the bone and soft tissue injuries for future definitive fixation and reconstructive procedures. In addition, external fixation about the knee has become a valuable tool as the definitive treatment for these high-energy injuries about the knee for the local population where limited resources are available for more definitive procedures. This article discusses important external fixation treatment principles that can be applied to civilian practices for the temporary and sometimes definitive care of fractures about the knee.
Stat5 Promotes Survival of Mammary Epithelial Cells through Transcriptional Activation of a Distinct Promoter in Akt1

ABSTRACT The signal transducer and activator of transcription 5 (Stat5) plays a pivotal role in the proliferation, secretory differentiation, and survival of mammary epithelial cells. However, there is little information about Stat5 target genes that facilitate these biological processes. We provide here experimental evidence that the prolactin-mediated phosphorylation of Stat5 regulates the transcriptional activation of the Akt1 gene. Stat5 binds to consensus sequences within the Akt1 locus in a growth factor-dependent manner to initiate transcription of a unique Akt1 mRNA from a distinct promoter, which is only active in the mammary gland. Elevating the levels of active Akt1 restores the expression of cyclin D1 and proliferation of Jak2-deficient mammary epithelial cells, which provides evidence that Akt1 acts downstream of Jak/Stat signaling. The ligand-inducible expression of Stat5 in transgenic females mediates a sustained upregulation of Akt1 in mammary epithelial cells during the onset of postlactational involution. Stat5-expressing mammary glands exhibit a delay in involution despite induction of proapoptotic signaling events. Collectively, the results of the present study elucidate an underlying mechanism by which active Stat5 mediates evasion from apoptosis and self-sufficiency in growth signals.
Kinematic characteristics of infant leg movements produced across a full day

Introduction Our purpose is to directly measure variability in infant leg movement behavior in the natural environment across a full day. We recently created an algorithm to identify an infant-produced leg movement from full-day wearable sensor data from infants with typical development between one and 12 months of age. Here we report the kinematic characteristics of their leg movements produced across a full day. Methods Wearable sensor data were collected from 12 infants with typical development for 8–13 h/day. A wearable sensor was attached to each ankle and recorded triaxial accelerometer and gyroscope measurements at 20 Hz. We determined the duration, average acceleration, and peak acceleration of each leg movement and classified its type (unilateral, bilateral synchronous, bilateral asynchronous). Results There was a range of leg movement duration (0.23–0.33 s) and acceleration (average 1.59–3.88 m/s2, peak 3.10–8.83 m/s2) values produced by infants across visits. Infants predominantly produced unilateral and asynchronous bilateral movements. Our results collected across a full day are generally comparable to kinematic measures obtained by other measurement tools across short periods of time. Conclusion Our results describe variable full-day kinematics of leg movements across infancy in a natural environment. These data create a reference standard for the future comparison of infants at risk for developmental delay.
Ocular blood flow and cerebrospinal fluid pressure in glaucoma

Disease mechanism underlying glaucoma remains unclear. Extensive research on this pathology has highlighted changes in vascular parameters and in circulation of the cerebrospinal fluid (CSF). Here, we review the most recent research on alterations in ocular blood flow and/or CSF flow in glaucoma. Ultrasound Doppler imaging studies have shown an increased resistive index in ophthalmic artery’s in glaucoma. Furthermore, changes in optic nerve CSF circulation, which can be assessed with magnetic resonance imaging, may lead to a greater translaminar pressure difference, mechanical stress, and poor clearance of toxic substances. This constitutes a new approach for understanding blood–CSF interactions involved in glaucoma.
The “Iowa Get Screened” Colon Cancer Screening Program

Objective: To implement a colon cancer screening program for uninsured or underinsured Iowans. Methods: All 1995 uninsured patients or patients with Iowa Care insurance aged 50 to 64 years attending the University of Iowa Clinic or the Iowa City Free Medical Clinic were mailed information about the project. Recruitment also took place in person, by having the clinic receptionist hand subjects a research packet, and through community posters. Individuals with colonic symptoms or who were up to date with screening were ineligible. Eligible subjects received a free fecal immunochemical test (FIT), and those with positive FITs were provided with a colonoscopy at no cost to them. Results: Of 449 individuals who completed eligibility forms (23% of the study population), 297 (66%) were eligible and were provided with an FIT. Two-hundred thirty-five (79%) returned a stool sample, with 49 (21%) testing positive. Thirty of the 49 (61%) individuals had a colonoscopy, and 20 individuals had at least 1 polyp biopsied. Thirteen individuals had at least 1 tubular adenoma; 2 had adenomas more than 1 cm in diameter, with no colon cancers identified. Face-to-face recruitment had the highest rate of returned FITs (72%) compared with handing the subject a research packet (3%) or a mailing only (9%) (Chi-square, P < .001). Conclusion: There was high interest in and compliance with colon cancer screening using a FIT among underinsured individuals. Although the FIT positivity rate was higher than expected, many individuals did not complete recommended follow-up colonoscopies. Population-based strategies for offering FIT could significantly increase colon cancer screening among disadvantaged individuals, but programs will have to develop sustainable mechanisms to include the necessary organization and address substantial costs of providing mass screening, as well as facilitating and providing colonoscopies for those who test positive.
PML Activates Transcription by Protecting HIPK2 and p300 from SCFFbx3-Mediated Degradation

ABSTRACT PML, a nuclear protein, interacts with several transcription factors and their coactivators, such as HIPK2 and p300, resulting in the activation of transcription. Although PML is thought to achieve transcription activation by stabilizing the transcription factor complex, little is known about the underlying molecular mechanism. To clarify the role of PML in transcription regulation, we purified the PML complex and identified Fbxo3 (Fbx3), Skp1, and Cullin1 as novel components of this complex. Fbx3 formed SCFFbx3 ubiquitin ligase and promoted the degradation of HIPK2 and p300 by the ubiquitin-proteasome pathway. PML inhibited this degradation through a mechanism that unexpectedly did not involve inhibition of the ubiquitination of HIPK2. PML, Fbx3, and HIPK2 synergistically activated p53-induced transcription. Our findings suggest that PML stabilizes the transcription factor complex by protecting HIPK2 and p300 from SCFFbx3-induced degradation until transcription is completed. In contrast, the leukemia-associated fusion PML-RARα induced the degradation of HIPK2. We discuss the roles of PML and PML-retinoic acid receptor α, as well as those of HIPK2 and p300 ubiquitination, in transcriptional regulation and leukemogenesis.
Implementation of a Diabetes Management Program for Patients in a Rural Primary Care Office

Objective: A diabetes management program was implemented in a rural primary care office for those who did not choose to consult a multidisciplinary specialty care. The purposes of this study were to describe the current practices and health care provider management of patients with diabetes in a rural primary care office and determine differences between Hispanic and non-Hispanic persons concerning diabetes self-care behaviors, barriers to self-care, and their association with glycosylated hemoglobin level. Methods: A retrospective medical record review of diabetes-related medical information was completed. Results: Sixty-one (74%) of the 83 patients with diabetes completed the questionnaire and had the diabetes management program implemented (problem summary and clinical summary generated). Medical record review was completed for 83 (100%) subjects. Glycosylated hemoglobin was significantly higher for the younger group and women. Hispanic women and married persons had significantly higher glycosylated hemoglobin than did non-Hispanic and unmarried persons. Hispanic persons who were obese had significantly higher glycosylated hemoglobin. Self-care behaviors for managing diabetes were different by group. Non-Hispanic subjects reported taking their diabetes medications 99% of the time and Hispanic subjects 50% of the time. Discussion: It was feasible to implement a diabetes management program in a rural primary care setting, and its implementation highlighted the ethnic differences for Hispanics and non-Hispanics in diabetes self-care behavior, barriers to self-care, and family support for diabetes management. The implementation of the diabetes management program, though, was time-consuming and costly and was facilitated outside of the usual realm of practice.
ALZHEIMER DISEASE: MALNUTRITION AND NUTRITIONAL SUPPORT

1 Alzheimer's disease (AD) is a degenerative disease of the central nervous system and its progression is often connected with a development of severe malnutrition. However, sufficient data on nutritional state and intervention regarding the progression of AD are not yet available. The aim of the present study was to assess the relationship between nutritional support and the improvement, or the maintenance, of patients’ health. 2 One hundred AD patients were included in a 2 year study. Voluntary food intake was measured during the first year, following which patients were randomized into one of two groups. The study group received a 600 kcal supplement to their regular diet, whereas the control group continued on the standard diet. Nutritional parameters, voluntary food intake and mental state were monitored every 2nd month of the study period. 3 Patients with Alzheimer's dementia who died had been suffering from severe malnutrition during the last 3 months of their lives. A significant decline in mental functions was discovered in AD patients also suffering from malnutrition. Nutritional support significantly slowed the deterioration of the mental function of AD patients. 4 The present study shows that patients with AD are undernourished despite normal voluntary energy intake. Nutritional intervention significantly decreased the progression of deterioration of the mental function of AD patients, as well as other complications. It is concluded that dietary counselling and nutritional support in patients with AD are clinically important and reduce the impairment of mental function.
TIA1 Prevents Skipping of a Critical Exon Associated with Spinal Muscular Atrophy

ABSTRACT Prevention of skipping of exon 7 during pre-mRNA splicing of Survival Motor Neuron 2 (SMN2) holds the promise for cure of spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. Here, we report T-cell-restricted intracellular antigen 1 (TIA1) and TIA1-related (TIAR) proteins as intron-associated positive regulators of SMN2 exon 7 splicing. We show that TIA1/TIAR stimulate exon recognition in an entirely novel context in which intronic U-rich motifs are separated from the 5′ splice site by overlapping inhibitory elements. TIA1 and TIAR are modular proteins with three N-terminal RNA recognition motifs (RRMs) and a C-terminal glutamine-rich (Q-rich) domain. Our results reveal that any one RRM in combination with a Q domain is necessary and sufficient for TIA1-associated regulation of SMN2 exon 7 splicing in vivo. We also show that increased expression of TIA1 counteracts the inhibitory effect of polypyrimidine tract binding protein, a ubiquitously expressed factor recently implicated in regulation of SMN exon 7 splicing. Our findings expand the scope of TIA1/TIAR in genome-wide regulation of alternative splicing under normal and pathological conditions.
Health 2.0—Lessons Learned

The advent of social networking as a major platform for human interaction has introduced a new dimension into the physician–patient relationship, known as Health 2.0. The concept of Health 2.0 is young and evolving; so far, it has meant the use of social media by health professionals and patients to personalize health care and promote health education. Social networking sites like Facebook and Twitter offer promising platforms for health care providers to engage patients. Despite the vast potential of Health 2.0, usage by health providers remains relatively low. Using a pilot study as an example, this commentary reviews the ways in which physicians can effectively harness the power of social networking to meaningfully engage their patients in primary prevention.
Providing Services for the High-Speed Train and Local Users in the Same OFDMA System: Resource Allocation in the Downlink

We consider providing broadband wireless services for passengers in a high-speed train and local users (low-mobility users) in the same OFDMA system. For the train, a two-hop architecture, under which, passengers communicate with base stations (BSs) via a mobile relay (MR) is employed. Then all passengers in the train can be treated as one large user represented by the MR. Since the channel conditions of the MR and local users are different in both large scale-fading and small-scale fading, we allocate the system resources over two time-scales for them. We formulate the resource allocation problem in the downlink OFDMA system as a capacity optimization problem for the MR subject to the sum capacity constraint of local users. We discuss the problem in two cases where perfect intercarrier interference (ICI) cancellation and no ICI cancellation are applied at the MR. The corresponding capacities and optimal power and subcarrier allocation (OPSA) policies are presented for each case. The capacities obtained in these two cases bound the achievable transmission rate of the MR and provide meaningful guidance for the application of ICI cancellation. Finally, the implementation issues of resource allocation policies are discussed to simplify application in practical scenarios.
Estrogen Receptors Recruit SMRT and N-CoR Corepressors through Newly Recognized Contacts between the Corepressor N Terminus and the Receptor DNA Binding Domain

ABSTRACT Estrogen receptors (ERs) are hormone-regulated transcription factors that regulate key aspects of reproduction and development. ERs are unusual in that they do not typically repress transcription in the absence of hormone but instead possess otherwise cryptic repressive functions that are revealed upon binding to certain hormone antagonists. The roles of corepressors in the control of these aspects of ER function are complex and incompletely understood. We report here that ERs recruit SMRT through an unusual mode of interaction involving multiple contact surfaces. Two surfaces of SMRT, located at the N- and C-terminal domains, contribute to the recruitment of the corepressor to ERs in vitro and are crucial for the corepressor modulation of ER transcriptional activity in cells. These corepressor surfaces contact the DNA binding domain of the receptor, rather than the hormone binding domain previously elucidated for other corepressor/nuclear receptor interactions, and are modulated by the ER's recognition of cognate DNA binding sites. Several additional nuclear receptors, and at least one other corepressor, N-CoR, share aspects of this novel mode of corepressor recruitment. Our results highlight a molecular mechanism that helps explain several previously paradoxical aspects of ER-mediated transcriptional antagonism, which may have a broader significance for an understanding of target gene repression by other nuclear receptors.
Comparing the Clinical Utility of the Infant Developmental Inventory With the Ages and Stages Questionnaire at 9-Month Well-Child Visits

Objective: The purpose of our study was to compare the clinical utility of administering 2 recommended developmental screening instruments, the Infant Developmental Inventory (IDI) and the Ages and Stages Questionnaire (ASQ), at 9-month well-child visits in paper format. Methods: Outcomes of the 2 screens, including correct completion and interpretation by clinician, time of visit, and screen outcome were compared. Results: Out of 33 children administered the ASQ and with documented scores, 12 (36.4%) did not receive passing scores, while 5 (12.2%) of the 41 children administered the IDI did not receive passing scores (P = .014). Out of 41 IDI screens, 12 (29.3%) were completed incorrectly, while there were no ASQ screens completed incorrectly (P < .001) by caregivers. Conclusion: In our pilot study, the ASQ is more often completed correctly by caregivers and identifies more children at risk for delay as compared with the IDI. Additional larger scale studies are needed to evaluate the usefulness of developmental screening tools when used within primary care practice.
Progenitor Stage-Specific Activity of a cis-Acting Double GATA Motif for Gata1 Gene Expression

ABSTRACT GATA1 is a master regulator of erythropoiesis, expression of which is regulated by multiple discrete cis-acting elements. In this study, we examine the activity of a promoter-proximal double GATA (dbGATA) motif, using a Gata1 bacterial artificial chromosome (BAC)-transgenic green fluorescent protein (GFP) reporter (G1BAC-GFP) mouse system. Deletion of the dbGATA motif led to significant reductions in GFP expression in hematopoietic progenitors, while GFP expression was maintained in erythroblasts. Consistently, in mice with a germ line deletion of the dbGATA motif (Gata1ΔdbGATA mice), GATA1 expression in progenitors was significantly decreased. The suppressed GATA1 expression was associated with a compensatory increase in GATA2 levels in progenitors. When we crossed Gata1ΔdbGATA mice with Gata2 hypomorphic mutant mice (Gata2fGN/fGN mice), the Gata1ΔdbGATA::Gata2fGN/fGN compound mutant mice succumbed to a significant decrease in the progenitor population, whereas both groups of single mutant mice maintained progenitors and survived to adulthood, indicating the functional redundancy between GATA1 and GATA2 in progenitors. Meanwhile, the effects of the dbGATA site deletion on Gata1 expression were subtle in erythroblasts, which showed increased GATA1 binding and enhanced accumulation of active histone marks around the 1st-intron GATA motif of the ΔdbGATA locus. These results thus reveal a novel role of the dbGATA motif in the maintenance of Gata1 expression in hematopoietic progenitors and a functional compensation between the dbGATA site and the 1st-intron GATA motif in erythroblasts.
TCPTP Regulates SFK and STAT3 Signaling and Is Lost in Triple-Negative Breast Cancers

ABSTRACT Tyrosine phosphorylation-dependent signaling, as mediated by members of the epidermal growth factor receptor (EGFR) family (ErbB1 to -4) of protein tyrosine kinases (PTKs), Src family PTKs (SFKs), and cytokines such as interleukin-6 (IL-6) that signal via signal transducer and activator of transcription 3 (STAT3), is critical to the development and progression of many human breast cancers. EGFR, SFKs, and STAT3 can serve as substrates for the protein tyrosine phosphatase TCPTP (PTPN2). Here we report that TCPTP protein levels are decreased in a subset of breast cancer cell lines in vitro and that TCPTP protein is absent in a large proportion of “triple-negative” primary human breast cancers. Homozygous TCPTP deficiency in murine mammary fat pads in vivo is associated with elevated SFK and STAT3 signaling, whereas TCPTP deficiency in human breast cancer cell lines enhances SFK and STAT3 signaling. On the other hand, TCPTP reconstitution in human breast cancer cell lines severely impaired cell proliferation and suppressed anchorage-independent growth in vitro and xenograft growth in vivo. These studies establish TCPTP's potential to serve as a tumor suppressor in human breast cancer.