Giardia Cyst Wall Protein 1 Is a Lectin That Binds to Curled Fibrils of the GalNAc Homopolymer

The infectious and diagnostic stage of Giardia lamblia (also known as G. intestinalis or G. duodenalis) is the cyst. The Giardia cyst wall contains fibrils of a unique β-1,3-linked N-acetylgalactosamine (GalNAc) homopolymer and at least three cyst wall proteins (CWPs) composed of Leu-rich repeats (CWPLRR) and a C-terminal conserved Cys-rich region (CWPCRR). Our goals were to dissect the structure of the cyst wall and determine how it is disrupted during excystation. The intact Giardia cyst wall is thin (~400 nm), easily fractured by sonication, and impermeable to small molecules. Curled fibrils of the GalNAc homopolymer are restricted to a narrow plane and are coated with linear arrays of oval-shaped protein complex. In contrast, cyst walls of Giardia treated with hot alkali to deproteinate fibrils of the GalNAc homopolymer are thick (~1.2 µm), resistant to sonication, and permeable. The deproteinated GalNAc homopolymer, which forms a loose lattice of curled fibrils, is bound by native CWP1 and CWP2, as well as by maltose-binding protein (MBP)-fusions containing the full-length CWP1 or CWP1LRR. In contrast, neither MBP alone nor MBP fused to CWP1CRR bind to the GalNAc homopolymer. Recombinant CWP1 binds to the GalNAc homopolymer within secretory vesicles of Giardia encysting in vitro. Fibrils of the GalNAc homopolymer are exposed during excystation or by treatment of heat-killed cysts with chymotrypsin, while deproteinated fibrils of the GalNAc homopolymer are degraded by extracts of Giardia cysts but not trophozoites. These results show the Leu-rich repeat domain of CWP1 is a lectin that binds to curled fibrils of the GalNAc homopolymer. During excystation, host and Giardia proteases appear to degrade bound CWPs, exposing fibrils of the GalNAc homopolymer that are digested by a stage-specific glycohydrolase. Author SummaryWhile the walls of plants and fungi contain numerous sugar homopolymers (cellulose, chitin, and β-1,3-glucans) and dozens of proteins, the cyst wall of Giardia is relatively simple. The Giardia wall contains a unique homopolymer of β-1,3-linked N-acetylgalactosamine (GalNAc) and at least three cyst wall proteins (CWPs), each of which is composed of Leu-rich repeats and a C-terminal Cys-rich region. The three major discoveries here are: 1) Fibrils of the GalNAc homopolymer are curled and form a lattice that is compressed into a narrow plane by bound protein in intact cyst walls. 2) Leu-rich repeats of CWP1 form a novel lectin domain that is specific for fibrils of the GalNAc homopolymer, which can be isolated by methods used to deproteinate fungal walls. 3) A cyst-specific glycohydrolase is able to degrade deproteinated fibrils of the GalNAc homopolymer. We incorporate these findings into a new curled fiber and lectin model of the intact Giardia cyst wall and a protease and glycohydrolase model of excystation.National Institutes of Health (AI048082, AI44070, GM31318, RR1088

Myonuclear Transcription is Responsive to Mechanical Load and DNA Content but Uncoupled from Cell Size During Hypertrophy

Myofibers increase size and DNA content in response to a hypertrophic stimulus, thus providing a physiological model with which to study how these factors affect global transcription. Using 5-ethynyl uridine (EU) to metabolically label nascent RNA, we measured a sevenfold increase in myofiber transcription during early hypertrophy before a change in cell size and DNA content. The typical increase in myofiber DNA content observed at the later stage of hypertrophy was associated with a significant decrease in the percentage of EU-positive myonuclei; however, when DNA content was held constant by preventing myonuclear accretion via satellite cell depletion, both the number of transcriptionally active myonuclei and the amount of RNA generated by each myonucleus increased. During late hypertrophy, transcription did not scale with cell size, as smaller myofibers (\u3c 1000 μm2) demonstrated the highest transcriptional activity. Finally, transcription was primarily responsible for changes in the expression of genes known to regulate myofiber size. These findings show that resident myonuclei possess a significant reserve capacity to up-regulate transcription during hypertrophy and that myofiber transcription is responsive to DNA content but uncoupled from cell size during hypertrophy

Slab-derived devolatilization fluids oxidized by subducted metasedimentary rocks

Metamorphic devolatilization of subducted slabs generates aqueous fluids that ascend into the mantle wedge, driving the partial melting that produces arc magmas. These magmas have oxygen fugacities some 10–1,000 times higher than magmas generated at mid-ocean ridges. Whether this oxidized magmatic character is imparted by slab fluids or is acquired during ascent and interaction with the surrounding mantle or crust is debated. Here we study the petrology of metasedimentary rocks from two Tertiary Aegean subduction complexes in combination with reactive transport modelling to investigate the oxidative potential of the sedimentary rocks that cover slabs. We find that the metasedimentary rocks preserve evidence for fluid-mediated redox reactions and could be highly oxidized. Furthermore, the modelling demonstrates that layers of these oxidized rocks less than about 200 m thick have the capacity to oxidize the ascending slab dehydration flux via redox reactions that remove H2, CH4 and/or H2S from the fluids. These fluids can then oxidize the overlying mantle wedge at rates comparable to arc magma generation rates, primarily via reactions involving sulfur species. Oxidized metasedimentary rocks need not generate large amounts of fluid themselves but could instead oxidize slab dehydration fluids ascending through them. Proposed Phanerozoic increases in arc magma oxygen fugacity may reflect the recycling of oxidative weathering products following Neoproterozoic–Palaeozoic marine and atmospheric oxygenation

Prevalence of the Use of Herbal Medicines among Patients with Cancer: A Systematic Review and Meta-Analysis

Background: Although herbal medicines are used by patients with cancer in multiple oncology care settings, the magnitude of herbal medicine use in this context remains unclear. )e purpose of this review was to establish the prevalence of herbal medicine use among patients with cancer, across various geographical settings and patient characteristics (age and gender categories). Methods: Electronic databases that were searched for data published, from January 2000 to January 2020, were Medline (PubMed), Google Scholar, Embase, and African Index Medicus. Eligible studies reporting prevalence estimates of herbal medicine use amongst cancer patients were pooled using random-effects meta-analyses. Studies were grouped by World Bank region and income groups. Subgroup and meta regression analyses were performed to explore source of heterogeneity. Results: In total, 155 studies with data for 809,065 participants (53.95% female) met the inclusion criteria. Overall, the pooled prevalence of the use of herbal medicine among patients with cancer was 22% (95% confidence interval (CI): 18%–25%), with the highest prevalence estimates for Africa (40%, 95% CI: 23%–58%) and Asia (28%, 95% CI: 21%–35%). )e pooled prevalence estimate was higher across low- and middle-income countries (32%, 95% CI: 23%–42%) and lower across high-income countries (17%, 95% CI: 14%–21%). Higher pooled prevalence estimates were found for adult patients with cancer (22%, 95% CI: 19%–26%) compared with children with cancer (18%, 95% CI: 11%–27%) and for female patients (27%, 95% CI: 19%–35%) compared with males (17%, 95% CI: 1%–47%). Conclusion: Herbal medicine is used by a large percentage of patients with cancer use. The findings of this review highlight the need for herbal medicine to be integrated in cancer care

The role of the hippocampus in passive and active spatial learning

Rats with lesions of the hippocampus or sham lesions were required in four experiments to escape from a square swimming pool by finding a submerged platform. Experiments 1 and 2 commenced with passive training in which rats were repeatedly placed on the platform in one corner—the correct corner—of a pool with distinctive walls. A test trial then revealed a strong preference for the correct corner in the sham but not the hippocampal group. Subsequent active training of being required to swim to the platform resulted in both groups acquiring a preference for the correct corner in the two experiments. In Experiments 3 and 4, rats were required to solve a discrimination between different panels pasted to the walls of the pool, by swimming to the middle of a correct panel. Hippocampal lesions prevented a discrimination being formed between panels of different lengths (Experiment 3), but not between panels showing lines of different orientations (Experiment 4); rats with sham lesions mastered both problems. It is suggested that an intact hippocampus is necessary for the formation of stimulus-goal associations that permit successful passive spatial leaning. It is further suggested that an intact hippocampus is not necessary for the formation of stimulus-response associations, except when they involve information about length or distance

Weather on the Nearest Brown Dwarfs: Resolved Simultaneous Multi-Wavelength Variability Monitoring of WISE J104915.57-531906.1AB

We present two epochs of MPG/ESO 2.2m GROND simultaneous 6-band ($r'i'z'JHK$) photometric monitoring of the closest known L/T transition brown dwarf binary WISE J104915.57-531906.1AB. We report here the first resolved variability monitoring of both the T0.5 and L7.5 components. We obtained 4 hours of focused observations on the night of UT 2013-04-22, as well as 4 hours of defocused (unresolved) observations on the night of UT 2013-04-16. We note a number of robust trends in our light curves. The $r'$ and $i'$ light curves appear to be anticorrelated with $z'$ and $H$ for the T0.5 component and in the unresolved lightcurve. In the defocused dataset, $J$ appears correlated with $z'$ and $H$ and anticorrelated with $r'$ and $i'$, while in the focused dataset we measure no variability for $J$ at the level of our photometric precision, likely due to evolving weather phenomena. In our focused T0.5 component lightcurve, the $K$ band lightcurve displays a significant phase offset relative to both $H$ and $z'$. We argue that the measured phase offsets are correlated with atmospheric pressure probed at each band, as estimated from 1D atmospheric models. We also report low-amplitude variability in $i'$ and $z'$ intrinsic to the L7.5 component.Comment: 14 pages, 5 figures, accepted to ApJ Letter

Ethnobotanical survey of medicinal plants used in the management of cancer in Uganda

Introduction: Patients with cancer in Africa embrace the use of herbal medicine more than anywhere else in the world. This study identified and documented medicinal plant species used to manage cancer in ten (10) districts of Uganda. Methods: An ethnobotanical survey was conducted between October 2021 and January 2022. In total, 18 (out of 55) traditional medicine practitioners (TMPs) having more than 10 years of experience in managing patients with cancer were interviewed using a semi-structured questionnaire. Data were analysed using descriptive statistics. The Relative frequency of citation (RFC) and Family importance value (FIV) indices were also computed. Results: We identified 121 plant species, belonging to 55 families, with the most common families being the Fabaceae (20 species, FIV = 0.119), Asteraceae (13 species, FIV = 0.131), and Euphorbiaceae (eight species, FIV = 0.079). The plant parts most commonly used were leaves (39.3%) and roots (12.9%). The most frequently cited plants were: Hoslundia opposita Vahl (RFC = 0.44), followed by Aspilia africana (Pers.) C.D. Adams (RFC = 0.33), Spathodea nilotica Seem (RFC = 0.33), Annona muricata L. (RFC = 0.33, Prunus africana (Hook.f.) Kalkman (RFC = 0.28), Acacia hockii De Wild (RFC = 0.28), Bidens pilosa L. (RFC = 0.28), and Carica papaya L (RFC = 0.22). The most common method of plant preparation and administration was the decoction (69.2%) and oral (86.7%) route, respectively. Conclusions: Although most plants used by TMPs have the potential to generate leads for chemo-preventive cancer medicines, they remain unexplored. This study provides a lead to explore the potential of traditionally used plants for the management of cancer through pre-clinical and clinical research

The association of mammographic density with risk of contralateral breast cancer and change in density with treatment in the WECARE study.

BACKGROUND: Mammographic density (MD) is an established predictor of risk of a first breast cancer, but the relationship of MD to contralateral breast cancer (CBC) risk is not clear, including the roles of age, mammogram timing, and change with treatment. Multivariable prediction models for CBC risk are needed and MD could contribute to these. METHODS: We conducted a case-control study of MD and CBC risk in phase II of the WECARE study where cases had a CBC diagnosed ≥ 2 years after first diagnosis at age <55 years and controls had unilateral breast cancer (UBC) with similar follow-up time. We retrieved film mammograms of the unaffected breast from two time points, prior to/at the time of the first diagnosis (253 CBC cases, 269 UBC controls) and ≥ 6 months up to 48 months following the first diagnosis (333 CBC cases, 377 UBC controls). Mammograms were digitized and percent MD (%MD) was measured using the thresholding program Cumulus. Odds ratios (OR) and 95% confidence intervals (CI) for association between %MD and CBC, adjusted for age, treatment, and other factors related to CBC, were estimated using logistic regression. Linear regression was used to estimate the association between treatment modality and change in %MD in 467 women with mammograms at both time points. RESULTS: For %MD assessed following diagnosis, there was a statistically significant trend of increasing CBC with increasing %MD (p = 0.03). Lower density (<25%) was associated with reduced risk of CBC compared to 25 to < 50% density (OR 0.69, 95% CI 0.49, 0.98). Similar, but weaker, associations were noted for %MD measurements prior to/at diagnosis. The relationship appeared strongest in women aged < 45 years and non-existent in women aged 50 to 54 years. A decrease of ≥ 10% in %MD between first and second mammogram was associated marginally with reduced risk of CBC (OR 0.63, 95% CI 0.40, 1.01) compared to change of <10%. Both tamoxifen and chemotherapy were associated with statistically significant 3% decreases in %MD (p < 0.01). CONCLUSIONS: Post-diagnosis measures of %MD may be useful to include in CBC risk prediction models with consideration of age at diagnosis. Chemotherapy is associated with reductions in %MD, similar to tamoxifen