Examples of Optical Assessment of Surface Cleanliness of Genesis Samples

Optical microscope assessment of Genesis solar wind collector surfaces is a coordinated part of the effort to obtain an assessed clean subset of flown wafer material for the scientific community. Microscopic survey is typically done at 50X magnification at selected approximately 1 square millimeter areas on the fragment surface. This survey is performed each time a principle investigator (PI) returns a sample to JSC for documentation as part of the established cleaning plan. The cleaning plan encompasses sample handling and analysis by Genesis science team members, and optical survey is done at each step in the process. Sample surface cleaning is performed at JSC (ultrapure water [1] and UV ozone cleaning [2]) and experimentally by other science team members (acid etch [3], acetate replica peels [4], CO2 snow [5], etc.). The documentation of each cleaning method can potentially be assessed with optical observation utilizing Image Pro Plus software [6]. Differences in particle counts can be studied and discussed within analysis groups. Approximately 25 samples have been identified as part of the cleaning matrix effort to date

Face valid phenotypes in a mouse model of the most common mutation in EEF1A2 related neurodevelopmental disorder, E122K

De novo heterozygous missense mutations in EEF1A2, encoding neuromuscular translation-elongation factor eEF1A2, are associated with developmental and epileptic encephalopathies. We used CRISPR/Cas9 to recapitulate the most common mutation, E122K, in mice. Although E122K heterozygotes were not observed to have convulsive seizures, they exhibited frequent electrographic seizures and EEG abnormalities, transient early motor deficits and growth defects. Both E122K homozygotes and Eef1a2-null mice developed progressive motor abnormalities, with E122K homozygotes reaching humane endpoints by P31. The null phenotype is driven by progressive spinal neurodegeneration; however, no signs of neurodegeneration were observed in E122K homozygotes. The E122K protein was relatively stable in neurons yet highly unstable in skeletal myocytes, suggesting that the E122K/E122K phenotype is instead driven by loss of function in muscle. Nevertheless, motor abnormalities emerged far earlier in E122K homozygotes than in nulls, suggesting a toxic gain of function and/or a possible dominant-negative effect. This mouse model represents the first animal model of an EEF1A2 missense mutation with face-valid phenotypes and has provided mechanistic insights needed to inform rational treatment design.</p

Reduction of the HIV-1 reservoir in resting CD4+ T-lymphocytes by high dosage intravenous immunoglobulin treatment: a proof-of-concept study

<p>Abstract</p> <p>Background</p> <p>The latency of HIV-1 in resting CD4⁺T-lymphocytes constitutes a major obstacle for the eradication of virus in patients on antiretroviral therapy (ART). As yet, no approach to reduce this viral reservoir has proven effective.</p> <p>Methods</p> <p>Nine subjects on effective ART were included in the study and treated with high dosage intravenous immunoglobulin (IVIG) for five consecutive days. Seven of those had detectable levels of replication-competent virus in the latent reservoir and were thus possible to evaluate. Highly purified resting memory CD4⁺T-cells were activated and cells containing replication-competent HIV-1 were quantified. HIV-1 from plasma and activated memory CD4⁺T-cells were compared with single genome sequencing (SGS) of the <it>gag </it>region. T-lymphocyte activation markers and serum interleukins were measured.</p> <p>Results</p> <p>The latent HIV-1 pool decreased with in median 68% after IVIG was added to effective ART. The reservoir decreased in five, whereas no decrease was found in two subjects with detectable virus. Plasma HIV-1 RNA ≥ 2 copies/mL was detected in five of seven subjects at baseline, but in only one at follow-up after 8–12 weeks. The decrease of the latent HIV-1 pool and the residual plasma viremia was preceded by a transitory low-level increase in plasma HIV-1 RNA and serum interleukin 7 (IL-7) levels, and followed by an expansion of T regulatory cells. The magnitude of the viral increase in plasma correlated to the size of the latent HIV-1 pool and SGS of the <it>gag </it>region showed that viral clones from plasma clustered together with virus from activated memory T-cells, pointing to the latent reservoir as the source of HIV-1 RNA in plasma.</p> <p>Conclusion</p> <p>The findings from this uncontrolled proof-of-concept study suggest that the reservoir became accessible by IVIG treatment through activation of HIV-1 gene expression in latently-infected resting CD4⁺T-cells. We propose that IVIG should be further evaluated as an adjuvant to effective ART.</p

Francisella tularensis Transmission by Solid Organ Transplantation, 20171.

In July 2017, fever and sepsis developed in 3 recipients of solid organs (1 heart and 2 kidneys) from a common donor in the United States; 1 of the kidney recipients died. Tularemia was suspected only after blood cultures from the surviving kidney recipient grew Francisella species. The organ donor, a middle-aged man from the southwestern United States, had been hospitalized for acute alcohol withdrawal syndrome, pneumonia, and multiorgan failure. F. tularensis subsp. tularensis (clade A2) was cultured from archived spleen tissue from the donor and blood from both kidney recipients. Whole-genome multilocus sequence typing indicated that the isolated strains were indistinguishable. The heart recipient remained seronegative with negative blood cultures but had been receiving antimicrobial drugs for a medical device infection before transplant. Two lagomorph carcasses collected near the donor's residence were positive by PCR for F. tularensis subsp. tularensis (clade A2). This investigation documents F. tularensis transmission by solid organ transplantation

Perceived discrimination and cancer screening behaviors in US Hispanics: the Hispanic Community Health Study/Study of Latinos Sociocultural Ancillary Study

Perceived discrimination has been associated with lower adherence to cancer screening guidelines. We examined whether perceived discrimination was associated with adherence to breast, cervical, colorectal, and prostate cancer screening guidelines in US Hispanic/Latino adults

Molecular Classification of Grade 3 Endometrioid Endometrial Cancers Identifies Distinct Prognostic Subgroups

Our aim was to investigate whether molecular classification can be used to refine prognosis in grade 3 endometrial endometrioid carcinomas (EECs). Grade 3 EECs were classified into 4 subgroups: p53 abnormal, based on mutant-like immunostaining (p53abn); MMR deficient, based on loss of mismatch repair protein expression (MMRd); presence of POLE exonuclease domain hotspot mutation (POLE); no specific molecular profile (NSMP), in which none of these aberrations were present. Overall survival (OS) and recurrence-free survival (RFS) rates were compared using the Kaplan-Meier method (Log-rank test) and univariable and multivariable Cox proportional hazard models. In total, 381 patients were included. The median age was 66 years (range, 33 to 96 y). Federation Internationale de Gynecologie et d'Obstetrique stages (2009) were as follows: IA, 171 (44.9%); IB, 120 (31.5%); II, 24 (6.3%); III, 50 (13.1%); IV, 11 (2.9%). There were 49 (12.9%) POLE, 79 (20.7%) p53abn, 115 (30.2%) NSMP, and 138 (36.2%) MMRd tumors. Median follow-up of patients was 6.1 years (range, 0.2 to 17.0 y). Compared to patients with NSMP, patients with POLE mutant grade 3 EEC (OS: hazard ratio [HR], 0.36 [95% confidence interval, 0.18-0.70]; P=0.003; RFS: HR, 0.17 [0.05-0.54]; P=0.003) had a significantly better prognosis; patients with p53abn tumors had a significantly worse RFS (HR, 1.73 [1.09-2.74]; P=0.021); patients with MMRd tumors showed a trend toward better RFS. Estimated 5-year OS rates were as follows: POLE 89%, MMRd 75%, NSMP 69%, p53abn 55% (Log rank P=0.001). Five-year RFS rates were as follows: POLE 96%, MMRd 77%, NSMP 64%, p53abn 47% (P=0.000001), respectively. In a multivariable Cox model that included age and Federation Internationale de Gynecologie et d'Obstetrique stage, POLE and MMRd status remained independent prognostic factors for better RFS; p53 status was an independent prognostic factor for worse RFS. Molecular classification of grade 3 EECs reveals that these tumors are a mixture of molecular subtypes of endometrial carcinoma, rather than a homogeneous group. The addition of molecular markers identifies prognostic subgroups, with potential therapeutic implications

Long-Term Habitat Degradation Drives Neotropical Macrophyte Species Loss While Assisting the Spread of Invasive Plant Species

The spread of invasive macrophyte species is a pressing threat to neotropical shallow lakes. Yet there are few studies addressing the full extent of biotic and abiotic changes that may occur in response to invasive species. Less is known of how other human-induced stressors such as eutrophication and lake draining may interact over time with invasive macrophytes to influence biodiversity. We combined limnological observations with paleoecological data from Fúquene Lake, Colombia, a eutrophic neotropical shallow lake, to provide information on the current and long-term (decades-centuries) dynamics of the spread of two well-established invasive plants Eichhornia crassipes and Egeria densa. We found a unique in macrophyte species composition in areas currently dominated by Egeria and Eichhornia. Eichhornia-dominated areas had 14 macrophyte species, turbid (secchi=19 ± 6 cm) and poorly oxygenated (3.94 ± 2.61 ppm) waters whereas Egeria-rich areas supported 5 species and had clearer (secchi=51 ± 12 cm) and better-oxygenated (6.06 ± 2.4 ppm) waters. Historical macrophyte community shifts were linked to eutrophication and lake level variation and characterized by the loss of charophytes and bryophytes before 1500 CE and subsequent reductions in Nymphaea sp., Potamogeton illinoensis and Najas guadalupensis in the early 1900s (lake draining). Eichhornia crassipes (since 1500 CE) and E. densa (early 1900s) occurred well before proposed dates of introduction (1950s and 1990 respectively). Both species have rapidly expanded since the 1990s along with Azolla filiculoides in response to an inflow water diversion scheme and heavy nutrient loads. Our results suggest that the spread of Eichhornia and Egeria was not responsible for native macrophyte species loss, but that their current dominance is exerting synergistic and antagonistic secondary effects on plant assemblages through habitat modification, competitive exclusion and promotion of habitat heterogeneity across the lake. It could therefore be misleading to suggest that invasive plants causes macrophyte species loss in degraded lakes. We suggest that aggressive species like Eichhornia, Azolla, and Egeria require hydrologically stable and eutrophic environments to spread; thus, management actions should focus on controlling these two factors. Our study demonstrates the need to use a long-term approach to fully-understand the effects of invasive macrophytes

Asymmetric thinning of the cerebral cortex across the adult lifespan is accelerated in Alzheimer’s disease

© 2021, The Author(s). Aging and Alzheimer’s disease (AD) are associated with progressive brain disorganization. Although structural asymmetry is an organizing feature of the cerebral cortex it is unknown whether continuous age- and AD-related cortical degradation alters cortical asymmetry. Here, in multiple longitudinal adult lifespan cohorts we show that higher-order cortical regions exhibiting pronounced asymmetry at age ~20 also show progressive asymmetry-loss across the adult lifespan. Hence, accelerated thinning of the (previously) thicker homotopic hemisphere is a feature of aging. This organizational principle showed high consistency across cohorts in the Lifebrain consortium, and both the topological patterns and temporal dynamics of asymmetry-loss were markedly similar across replicating samples. Asymmetry-change was further accelerated in AD. Results suggest a system-wide dedifferentiation of the adaptive asymmetric organization of heteromodal cortex in aging and AD