Additive manufacturing is distinguished from traditional manufacturing techniques such as casting and machining by its ability to handle complex shapes with great design flexibility and without the ...typical waste. Although this technique has been mainly used for rapid prototyping, interest is growing in direct manufacture of actual parts. For wide spread application of 3D additive manufacturing, both techniques and feedstock materials require improvements to meet the mechanical requirements of load-bearing components. Here, we investigated short fiber (0.2–0.4mm) reinforced acrylonitrile–butadiene–styrene composites as a feedstock for 3D-printing in terms of their processibility, microstructure and mechanical performance. The additive components are also compared with traditional compression molded composites. The tensile strength and modulus of 3D-printed samples increased ∼115% and ∼700%, respectively. 3D-printing yielded samples with very high fiber orientation in the printing direction (up to 91.5%), whereas, compression molding process yielded samples with significantly lower fiber orientation. Microstructure–mechanical property relationships revealed that although a relatively high porosity is observed in 3D-printed composites as compared to those produced by the conventional compression molding technique, they both exhibited comparable tensile strength and modulus. This phenomenon is explained based on the changes in fiber orientation, dispersion and void formation.
This study describes a non-dilutive high-gradient magnetic separation (HGMS) device intended to continuously remove malaria-infected red blood cells (iRBCs) from the circulation. A mesoscale ...prototype device with disposable photo-etched ferromagnetic grid and reusable permanent magnet was designed with a computationally-optimized magnetic force. The prototype device was evaluated
in vitro
using a non-pathogenic analog for malaria-infected blood, comprised of 24% healthy RBCs, 6% human methemoglobin RBCs (metRBCs), and 70% phosphate buffer solution (PBS). The device provided a 27.0 ± 2.2% reduction of metRBCs in a single pass at a flow rate of 77
μ
L min
−1
. This represents a clearance rate over 380 times greater throughput than microfluidic devices reported previously. These positive results encourage development of a clinical scale system that would economize time and donor blood for treating severe malaria.
When confronted with poor oxygenation, cells adapt by activating survival signaling pathways, including the oxygen-sensitive transcriptional regulators called hypoxia-inducible factor alphas ...(HIF-αs). We report here that HIF-1α also regulates the life cycle of Epstein-Barr virus (EBV). Incubation of EBV-positive gastric carcinoma AGS-Akata and SNU-719 and Burkitt lymphoma Sal and KemIII cell lines with a prolyl hydroxylase inhibitor, L-mimosine or deferoxamine, or the NEDDylation inhibitor MLN4924 promoted rapid and sustained accumulation of both HIF-1α and lytic EBV antigens. ShRNA knockdown of HIF-1α significantly reduced deferoxamine-mediated lytic reactivation. HIF-1α directly bound the promoter of the EBV primary latent-lytic switch BZLF1 gene, Zp, activating transcription via a consensus hypoxia-response element (HRE) located at nt -83 through -76 relative to the transcription initiation site. HIF-1α did not activate transcription from the other EBV immediate-early gene, BRLF1. Importantly, expression of HIF-1α induced EBV lytic-gene expression in cells harboring wild-type EBV, but not in cells infected with variants containing base-pair substitution mutations within this HRE. Human oral keratinocyte (NOK) and gingival epithelial (hGET) cells induced to differentiate by incubation with either methyl cellulose or growth in organotypic culture accumulated both HIF-1α and Blimp-1α, another cellular factor implicated in lytic reactivation. HIF-1α activity also accumulated along with Blimp-1α during B-cell differentiation into plasma cells. Furthermore, most BZLF1-expressing cells observed in lymphomas induced by EBV in NSG mice with a humanized immune system were located distal to blood vessels in hypoxic regions of the tumors. Thus, we conclude that HIF-1α plays central roles in both EBV's natural life cycle and EBV-associated tumorigenesis. We propose that drugs that induce HIF-1α protein accumulation are good candidates for development of a lytic-induction therapy for treating some EBV-associated malignancies.
Abstract
Study Objectives
The aim of this study was to characterize the sleep disorders of insomnia, obstructive sleep apnea (OSA), and comorbid insomnia and OSA (COMISA) in active duty military ...personnel.
Methods
Prospective observational study of 309 military personnel with a mean age of 37.17 years (SD = 7.27). Participants served in four branches of the U.S. military (47.9% Air Force, 38.8% Army, 11.3% Navy, and 1.9% Marines). Sleep diagnoses were rendered after video-polysomnography and a clinical evaluation. Validated self-report measures assessed insomnia severity, excessive daytime sleepiness, sleep quality, disruptive nocturnal behaviors, nightmare disorder, shift work disorder (SWD), sleep impairment, fatigue, posttraumatic stress disorder (PTSD) symptoms, anxiety, depression, and traumatic brain injury (TBI). General linear models and Pearson chi-square tests were used for between-group differences in data analyses.
Results
Insomnia was diagnosed in 32.7%, OSA in 30.4% and COMISA in 36.9%. Compared to military personnel with OSA alone, those with insomnia only and COMISA had significantly greater insomnia severity, disruptive nocturnal behaviors, sleep-related impairment, rates of nightmare disorder, and poorer sleep quality (all Ps < .05). They also reported greater symptoms of fatigue, PTSD, anxiety, and depression (all Ps < .05). There were no significant differences among the three sleep disorder diagnostic groups on sleepiness, SWD, or TBI.
Conclusions
Military personnel with insomnia only and COMISA overall report worsened symptoms of sleep disorders, sleep-related impairment, fatigue, and psychiatric disorders than those with OSA. Results highlight the importance of a comprehensive assessment for sleep-related impairment, sleep, and comorbid disorders in military personnel with clinically significant sleep disturbances.
Graphical Abstract
Graphical Abstract
The Peruvian Amazon is an important arena in global efforts to promote sustainable logging in the tropics. Despite recent efforts to achieve sustainability, such as provisions in the US-Peru Trade ...Promotion Agreement, illegal logging continues to plague the region. We present evidence that Peru's legal logging concession system is enabling the widespread illegal logging via the regulatory documents designed to ensure sustainable logging. Analyzing official government data, we found that 68.3% of all concessions supervised by authorities were suspected of major violations. Of the 609 total concessions, nearly 30% have been cancelled for violations and we expect this percentage to increase as investigations continue. Moreover, the nature of the violations indicate that the permits associated with legal concessions are used to harvest trees in unauthorized areas, thus threatening all forested areas. Many of the violations pertain to the illegal extraction of CITES-listed timber species outside authorized areas. These findings highlight the need for additional reforms.
We previously reported that the cellular transcription factor hypoxia-inducible factor 1α (HIF-1α) binds a hypoxia response element (HRE) located within the promoter of Epstein-Barr virus's (EBV's) ...latent-lytic switch
gene, Zp, inducing viral reactivation. In this study, EBV-infected cell lines derived from gastric cancers and Burkitt lymphomas were incubated with HIF-1α-stabilizing drugs: the iron chelator deferoxamine (Desferal DFO), a neddylation inhibitor (pevonedistat MLN-4924), and a prolyl hydroxylase inhibitor (roxadustat FG-4592). DFO and MLN-4924, but not FG-4592, induced accumulation of both lytic EBV proteins and phosphorylated p53 in cell lines that contain a wild-type p53 gene. FG-4592 also failed to activate transcription from Zp in a reporter assay despite inducing accumulation of HIF-1α and transcription from another HRE-containing promoter. Unexpectedly, DFO failed to induce EBV reactivation in cell lines that express mutant or no p53 or when p53 expression was knocked down with short hairpin RNAs (shRNAs). Likewise, HIF-1α failed to activate transcription from Zp when p53 was knocked out by CRISPR-Cas9. Importantly, DFO induced binding of p53 as well as HIF-1α to Zp in chromatin immunoprecipitation (ChIP) assays, but only when the HRE was present. Nutlin-3, a drug known to induce accumulation of phosphorylated p53, synergized with DFO and MLN-4924 in inducing EBV reactivation. Conversely, KU-55933, a drug that inhibits ataxia telangiectasia mutated, thereby preventing p53 phosphorylation, inhibited DFO-induced EBV reactivation. Lastly, activation of Zp transcription by DFO and MLN-4924 mapped to its HRE. Thus, we conclude that induction of
gene expression by HIF-1α requires phosphorylated, wild-type p53 as a coactivator, with HIF-1α binding recruiting p53 to Zp.
EBV, a human herpesvirus, is latently present in most nasopharyngeal carcinomas, Burkitt lymphomas, and some gastric cancers. To develop a lytic-induction therapy for treating patients with EBV-associated cancers, we need a way to efficiently reactivate EBV into lytic replication. EBV's
gene product, Zta, usually controls this reactivation switch. We previously showed that HIF-1α binds the
gene promoter, inducing Zta synthesis, and HIF-1α-stabilizing drugs can induce EBV reactivation. In this study, we determined which EBV-positive cell lines are reactivated by classes of HIF-1α-stabilizing drugs. We found, unexpectedly, that HIF-1α-stabilizing drugs only induce reactivation when they also induce accumulation of phosphorylated, wild-type p53. Fortunately, p53 phosphorylation can also be provided by drugs such as nutlin-3, leading to synergistic reactivation of EBV. These findings indicate that some HIF-1α-stabilizing drugs may be helpful as part of a lytic-induction therapy for treating patients with EBV-positive malignancies that contain wild-type p53.
The ATLAS experiment is going to replace the current Inner Detector with an all new inner tracker (ITk) in the ATLAS detector for HL-LHC at CERN. Silicon strip detectors cover the outer layers of the ...barrel and the endcap sections. We have designed and fabricated a prototype single-sided n+-in-p AC-coupled silicon strip sensor for the outer barrel layer with long strips (LS), ATLAS17LS. It is of the maximum allowable size to fit in a 6-in. silicon wafer, with an outer dimension of 9.80(width)×9.76(length)cm2. The sensor features two rows of LS strip segments, 4.83 cm strip length per segment, a strip pitch of 75.5 μm, and a slim edge design. We have implemented technology for high voltage operation of up to 1000V, with a good signal collection after irradiation fluence of 5.6 × 1014neq∕cm2at the end of HL-LHC operation.
We had two objectives for the ATLAS17LS fabrication: qualification of the sensor design and fabrication quality, and providing an adequate number of the sensors for prototyping the building blocks of the strip detector. The sensors were fabricated in 3 batches by HPK with standard wafers from the foundry (320 μm physical thickness). Additional 10 sensors were fabricated with a thinner active thickness of 240 μm to investigate the influence of active thickness on charge collection. Another additional 5 sensors, with special passivation to investigate the influence of passivation on humidity sensitivity. The visual inspection of fabricated sensors revealed an inadequacy that the designed metal width of 10 μm was too narrow. The initial measurements by the vendor showed that the sensors fulfilled the specifications: onset voltages of Microdischarge VMD above the operation voltage VOP (700V for the 1st and 2nd batches; 500V for the 3rd batch, which has improved the yield), leakage currents of < 0.1μA/cm2 at VOP, full depletion voltages VFD< 330V, and rates of bad strips <<1%.
Latent infection of Epstein-Barr virus (EBV) is associated with lymphoid and epithelial cell cancers, including 10% of gastric carcinomas. We previously reported that hypoxia inducible factor-1α ...(HIF-1α) induces EBV's latent-to-lytic switch and identified several HIF-1α-stabilizing drugs that induce this viral reactivation. Here, we tested three classes of these drugs for preferential killing of the EBV-positive gastric cancer AGS-Akata cell line compared to its matched EBV-negative AGS control. We observed preferential killing with iron chelators Deferoxamine (DFO); Deferasirox (DFX) and a prolyl hydroxylase inhibitor (BAY 85-3934 (Molidustat)), but not with a neddylation inhibitor MLN4924 (Pevonedistat). DFO and DFX also induced preferential killing of the EBV-positive gastric cancer AGS-BDneo and SNU-719 cell lines. Preferential killing was enhanced when low-dose DFX (10 μM) was combined with the antiviral prodrug ganciclovir. DFO and DFX induced lytic EBV reactivation in approximately 10% of SNU-719 and 20-30% of AGS-Akata and AGS-BDneo cells. However, neither DFO nor DFX significantly induced synthesis of lytic EBV proteins in xenografts grown in NSG mice from AGS-Akata cells above the level observed in control-treated mice. Therefore, these FDA-approved iron chelators are less effective than gemcitabine at promoting EBV reactivation in vivo despite their high specificity and efficiency in vitro.
The aim of this study was to evaluate sex-related differences in symptoms of sleep disorders, sleep-related impairment, psychiatric symptoms, traumatic brain injury, and polysomnographic variables in ...treatment-seeking military personnel diagnosed with insomnia, obstructive sleep apnea (OSA), or comorbid insomnia and OSA (COMISA).
Participants were 372 military personnel (46.2% women, 53.8% men) with an average age of 37.7 (standard deviation = 7.46) years and median body mass index of 28.4 (5.50) kg/m
. Based on clinical evaluation and video-polysomnography, participants were diagnosed with insomnia (n = 118), OSA (n = 118), or COMISA (n = 136). Insomnia severity, excessive daytime sleepiness, sleep quality, nightmare disorder, sleep impairment, fatigue, posttraumatic stress disorder, anxiety, depression symptoms, and traumatic brain injury were evaluated with validated self-report questionnaires. Descriptive statistics, parametric and nonparametric
-tests, and effect sizes were used to assess sex differences between men and women.
There were no significant differences between women and men with insomnia or OSA in sleep-related symptoms, impairment, or polysomnography-based apnea-hypopnea index. Military men with COMISA had a significantly greater apnea-hypopnea index as compared to military women with COMISA, but women had greater symptoms of nightmare disorder, posttraumatic stress disorder, and anxiety.
In contrast to civilian studies, minimal differences were observed in self-reported sleep symptoms, impairment, and polysomnography metrics between men and women diagnosed with the most frequent sleep disorders in military personnel (ie, insomnia, OSA, or COMISA) except in those with COMISA. Military service may result in distinct sleep disorder phenotypes that differ negligibly by sex.
Mysliwiec V, Pruiksma KE, Matsangas P, et al. Sex differences in US military personnel with insomnia, obstructive sleep apnea, or comorbid insomnia and obstructive sleep apnea.
. 2024;20(1):17-30.
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