Week 7 in the Books!
Fellow Abstract Watchers! I just selected and am listing my week 7 abstracts and going through them now :) It has been that kind of week.
Lots of interesting stuff here. I'm personally interested in #47 (easy tests for isolated impaired glucose tolerance b/c I monitor my blood sugar since it's remained relatively high since gestational diabetes), #46 (essentially vigorous chores around the house substantially reduce your risk of death & disease), #45 (nuclear pore regulation controls nuclear transport of maternal transcription factors & zygotic genome activation). and #44 (of course none of our antibodies are any good against new SARS-CoV-2 subvariants, let's just hope disease is less severe?!).
Abstract 42: Ovarian cancer mutational processes drive site-specific immune evasion open access and posted on biorxiv about 15 months earlier (with the title "Immune and malignant cell phenotypes of ovarian cancer are determined by distinct mutational processes").
Take home: Immunotherapies have had limited efficacy in ovarian cancer, and how mutational processes and the anatomical sites of tumour foci determine the immunological states of the tumour microenvironment are not known. The authors found that homologous recombination-deficient HRD-Dup (BRCA1 mutant-like) and HRD-Del (BRCA2 mutant-like) tumours harboured inflammatory signalling and ongoing immunoediting, reflected in loss of HLA diversity and tumour infiltration with highly differentiated dysfunctional CD8+ T cells. By contrast, foldback-inversion-bearing tumours exhibited elevated immunosuppressive TGFβ signalling and immune exclusion, with predominantly naive/stem-like and memory T cells. Phenotypic state associations were specific to anatomical sites, highlighting compositional, topological and functional differences between adnexal tumours and distal peritoneal foci. The findings implicate anatomical sites and mutational processes as determinants of evolutionary phenotypic divergence and immune resistance mechanisms in HGSOC.
Abstract 43: A male germ-cell-specific ribosome controls male fertility open access no preprint.
Take home: A ribosome with a specialized nascent polypeptide exit tunnel, RibosomeST, is assembled with the male germ-cell-specific protein RPL39L, the paralogue of core ribosome (RibosomeCore) protein RPL39. Deletion of RibosomeST in mice causes defective sperm formation, resulting in substantially reduced fertility. RibosomeST features a ribosomal polypeptide exit tunnel of distinct size and charge states compared with RibosomeCore. RibosomeST predominantly cotranslationally regulates the folding of a subset of male germ-cell-specific proteins that are essential for the formation of sperm. Specialized functions of RibosomeST were not replaceable by RibosomeCore.
Abstract 44: Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants not open access, on biorxiv a couple of weeks before publication.
Take home: The BQ and XBB subvariants of SARS-CoV-2 Omicron are now rapidly expanding. Neutralization of BQ.1, BQ.1.1, XBB, and XBB.1 by sera from vaccinees and infected persons was markedly impaired, including sera from individuals boosted with a WA1/BA.5 bivalent mRNA vaccine. Monoclonal antibodies capable of neutralizing the original Omicron variant were largely inactive against these new subvariants.These subvariants were found to have similar ACE2-binding affinities as their predecessors. Together, our findings indicate that BQ and XBB subvariants present serious threats to current COVID-19 vaccines, render inactive all authorized antibodies, and may have gained dominance in the population because of their advantage in evading antibodies. ("Great")
Abstract 45: Comprehensive maturity of nuclear pore complexes regulates zygotic genome activation open access, no preprint.
Take home: Comprehensive NPC maturity (CNM) controls the onset of zygotic genome activation (ZGA) during zebrafish early embryogenesis. We show that more nucleoporin proteins are recruited to and assembled into NPCs with development, resulting in progressive increase of NPCs in size and complexity. Maternal transcription factors (TFs) transport into nuclei more efficiently with increasing CNM. Deficiency or dysfunction of Nup133 or Ahctf1/Elys impairs NPC assembly, maternal TFs nuclear transport, and ZGA onset, while nup133 overexpression promotes these processes. Therefore, CNM may act as a molecular timer for ZGA by controlling nuclear transport of maternal TFs that reach nuclear concentration thresholds at a given time to initiate ZGA.
Abstract 46: Association of wearable device-measured vigorous intermittent lifestyle physical activity with mortality open access, no preprint.
Take home: Wearable devices can capture unexplored movement patterns such as brief bursts of vigorous intermittent lifestyle physical activity (VILPA) that is embedded into everyday life, rather than being done as leisure time exercise. Examined the association of VILPA with all-cause, cardiovascular disease (CVD) and cancer mortality in 25,241 nonexercisers (mean age 61.8 years, 14,178 women/11,063 men) in the UK Biobank. Over an average follow-up of 6.9 years, during which 852 deaths occurred, VILPA was inversely associated with all three of these outcomes in a near-linear fashion. Compared with participants who engaged in no VILPA, participants who engaged in VILPA at the sample median VILPA frequency of 3 length-standardized bouts per day (lasting 1 or 2 min each) showed a 38%–40% reduction in all-cause and cancer mortality risk and a 48%–49% reduction in CVD mortality risk. ... VILPA in nonexercisers appears to elicit similar effects to VPA in exercisers, suggesting that VILPA may be a suitable physical activity target, especially in people not able or willing to exercise. (This makes me feel really good about carrying shopping bags, going up and downstairs with laundry, vacuuming etc ;) )
Abstract 47: Proteomic signatures for identification of impaired glucose tolerance open access, no preprint.
Take home: The implementation of recommendations for type 2 diabetes (T2D) screening and diagnosis focuses on the measurement of glycated hemoglobin (HbA1c) and fasting glucose. This approach leaves a large number of individuals with isolated impaired glucose tolerance (iIGT), who are only detectable through oral glucose tolerance tests (OGTTs), at risk of diabetes and its severe complications (me!!). We applied machine learning to the proteomic profiles of a single fasted sample from 11,546 participants of the Fenland study to test discrimination of iIGT defined using the gold-standard OGTTs. We observed significantly improved discriminative performance by adding only three proteins (RTN4R, CBPM and GHR) to the best clinical model (AUROC = 0.80 (95% confidence interval: 0.79–0.86), P = 0.004), which we validated in an external cohort. Increased plasma levels of these candidate proteins were associated with an increased risk for future T2D in an independent cohort and were also increased in individuals genetically susceptible to impaired glucose homeostasis and T2D. Assessment of a limited number of proteins can identify individuals likely to be missed by current diagnostic strategies and at high risk of T2D and its complications. (This is great, we need an easy test for 'glucose excursions'....)
Abstract 48: Mechanistic insight into female predominance in Alzheimer’s disease based on aberrant protein S-nitrosylation of C3 open access, no preprint.
Take home: Protein S-nitros(yl)ation (SNO) is a posttranslational modification... can contribute to synaptic damage in Alzheimer’s disease (AD). To identify SNO proteins in AD brains, we used triaryl phosphine (SNOTRAP) combined with mass spectrometry (MS). We detected 1449 SNO proteins with 2809 SNO sites in AD and non-AD human brains from patients of both sexes. Integrative protein ranking revealed the top 10 increased SNO proteins, including complement component 3 (C3), p62 (SQSTM1), and phospholipase D3. Increased levels of S-nitrosylated C3 were present in female over male AD brains. Mechanistically, we show that formation of SNO-C3 is dependent on falling β-estradiol levels, leading to increased synaptic phagocytosis and thus synapse loss and consequent cognitive decline. Collectively, we demonstrate robust alterations in the S-nitrosoproteome that contribute to AD pathogenesis in a sex-dependent manner. (due to falling estrogen?! - will have to read this one....)