Score: 6.4, Published: 2024-02-12
DOI: 10.1101/2024.02.08.579567
Female carriers of a Duchenne muscular dystrophy (DMD) gene mutation manifest exercise intolerance and metabolic anomalies that may be exacerbated following menopause due to the loss of estrogen, a known regulator of skeletal muscle function and metabolism. Here, we studied the impact of estrogen depletion (via ovariectomy) on exercise tolerance and muscle mitochondrial metabolism in female mdx mice and the potential of estrogen replacement therapy (using estradiol) to protect against functional and metabolic perturbations. We also investigated the effect of estrogen depletion, and replacement, on the skeletal muscle proteome through an untargeted proteomic approach with TMT-labelling. Our study confirms that loss of estrogen in female mdx mice reduces exercise capacity, tricarboxylic acid cycle intermediates and citrate synthase activity but that these deficits can be offset through estrogen replacement therapy. Furthermore, ovariectomy downregulated protein expression of RNA binding motif factor 20 (Rbm20), a critical regulator of sarcomeric and muscle homeostasis gene splicing, which impacted pathways involving ribosomal and mitochondrial translation. Estrogen replacement modulated Rbm20 protein expression and promoted metabolic processes and the upregulation of proteins involved in mitochondrial dynamics and metabolism. Our data suggests that estrogen mitigates dystrophinopathic features in female mdx mice and that estrogen replacement may be a potential therapy for post-menopausal DMD carriers.
Score: 1.2, Published: 2024-02-16
DOI: 10.1101/2024.02.15.580423
Leptosphaeria maculans is one of the major fungal pathogens on oilseed rape (Brassica napus), causing stem canker disease. The closely related Brassica species Brassica nigra, Brassica juncea, and Brassica carinata display extreme resistance toward stem canker. In this study, we demonstrate the nonhost status of B. carinata toward L. maculans in France through field experiments and inoculations performed in controlled conditions. A few isolates moderately adapted to B. carinata, in controlled conditions, were recovered in the field on B. nigra leaves, allowing us to investigate the unusual B. carinata / L. maculans interactions using molecular, macroscopic, and microscopic analyses. A cross between a L. maculans isolate adapted to B. napus and an isolate moderately adapted to B. carinata allowed the generation, in the lab, of recombinant L. maculans strains better adapted to B. carinata than the natural parental isolate obtained from B. nigra, and highlighted the polygenic determinism of the adaptation of L. maculans to B. carinata and B. napus. This biological material will allow further investigation of the molecular determinants of the adaptation of L. maculans to nonhost species and elucidate the genetic resistance basis of B. carinata.
Score: 1.0, Published: 2024-02-16
DOI: 10.1101/2024.02.13.579999
Importance: This study identifies and quantifies diverse pathological tau isoforms in the retina of both early and advanced-stage Alzheimer's disease (AD) and determines their relationship with disease status. Objective: A case-control study was conducted to investigate the accumulation of retinal neurofibrillary tangles (NFTs), paired helical filament (PHF)-tau, oligomeric tau (oligo-tau), hyperphosphorylated tau (p-tau), and citrullinated tau (Cit-tau) in relation to the respective brain pathology and cognitive dysfunction in mild cognitively impaired (MCI) and AD dementia patients versus normal cognition (NC) controls. Design, setting and participants: Eyes and brains from donors diagnosed with AD, MCI (due to AD), and NC were collected (n=75 in total), along with clinical and neuropathological data. Brain and retinal cross-sections-in predefined superior-temporal and inferior-temporal (ST/IT) subregions-were subjected to histopathology analysis or Nanostring GeoMx digital spatial profiling. Main outcomes and measure: Retinal burden of NFTs (pretangles and mature tangles), PHF-tau, p-tau, oligo-tau, and Cit-tau was assessed in MCI and AD versus NC retinas. Pairwise correlations revealed associations between retinal and brain parameters and cognitive status. Results: Increased retinal NFTs (1.8-fold, p=0.0494), PHF-tau (2.3-fold, p<0.0001), oligo-tau (9.1-fold, p<0.0001), CitR209-tau (4.3-fold, p<0.0001), pSer202/Thr205-tau (AT8; 4.1-fold, p<0.0001), and pSer396-tau (2.8-fold, p=0.0015) were detected in AD patients. Retinas from MCI patients showed significant increases in NFTs (2.0-fold, p=0.0444), CitR209-tau (3.5-fold, p=0.0201), pSer396-tau (2.6-fold, p=0.0409), and, moreover, oligo-tau (5.8-fold, p=0.0045). Nanostring GeoMx quantification demonstrated upregulated retinal p-tau levels in MCI patients at phosphorylation sites of Ser214 (2.3-fold, p=0.0060), Ser396 (1.8-fold, p=0.0052), Ser404 (2.4-fold, p=0.0018), and Thr231 (3.3-fold, p=0.0028). Strong correlations were found between retinal tau forms to paired-brain pathology and cognitive status: a) retinal oligo-tau vs. Braak stage (r=0.60, P=0.0002), b) retinal PHF-tau vs. ABC average score (r=0.64, P=0.0043), c) retinal pSer396-tau vs. brain NFTs (r=0.68, P<0.0001), and d) retinal pSer202/Thr205-tau vs. MMSE scores (r= -0.77, P=0.0089). Conclusions and Relevance: This study reveals increases in immature and mature retinal tau isoforms in MCI and AD patients, highlighting their relationship with brain pathology and cognition. The data provide strong incentive to further explore retinal tauopathy markers that may be useful for early detection and monitoring of AD staging through noninvasive retinal imaging.
Score: 1.0, Published: 2024-02-12
DOI: 10.1101/2024.02.11.579823
Peripheral arterial disease can cause limb threatening blood flow restriction, requiring amputation in up to a third of patients despite contemporary treatments. Stimulating new blood vessel growth in ischemic limbs using growth factors such as VEGF-A or supplying mixed cell populations via autologous transplantation has been investigated as a therapy for surgically intractable cases, but to date has proven ineffective in randomised controlled clinical studies. To identify more potent pro-arteriogenic cell populations, we have investigated VEGF-A responsive myeloid cell populations in a mouse model of severe hindlimb ischemia. We found that NRP1 ablation from monocytes and macrophages impaired arteriogenesis in the adductor muscle and flow recovery in the injured limb. Vice versa, the exogenous delivery of NRP1-expressing (but not NRP1-negative) macrophages enhanced arteriogenesis in the adductor and flow recovery in the ischemic limb in a VEGF signalling-dependent manner. Further, patient-derived NRP1-expressing monocytes promoted vascular morphogenesis ex vivo. As the levels of circulating NRP1-expressing monocytes were raised in patients with limb ischemia, the therapeutic delivery of autologous NRP1-expressing monocytes could be explored as a treatment for critical limb ischemia.