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Mitochondrial topoisomerase IB (TOP1MT) is a nuclear-encoded topoisomerase, exclusively localized to mitochondria, which resolves topological stress generated during mtDNA replication and transcription. Here, we report that TOP1MT is overexpressed in cancer tissues and demonstrate that TOP1MT deficiency attenuates tumor growth in human and mouse models of colon and liver cancer. Due to their mitochondrial dysfunction, TOP1MT-KO cells become addicted to glycolysis, which limits synthetic building blocks and energy supply required for the proliferation of cancer cells in a nutrient-deprived tumor microenvironment. Mechanistically, we show that TOP1MT associates with mitoribosomal subunits, ensuring optimal mitochondrial translation and assembly of oxidative phosphorylation complexes that are critical for sustaining tumor growth. The TOP1MT genomic signature profile, based on Top1mt -KO liver cancers, is correlated with enhanced survival of hepatocellular carcinoma patients. Our results highlight the importance of TOP1MT for tumor development, providing a potential rationale to develop TOP1MT-targeted drugs as anticancer therapies. TOP1MT is a topoisomerase that is localised to mitochondria. Here, the authors show that TOP1MT has a tumor promoting role in hepatocellular carcinoma by supporting mitochondrial translation and that its deficiency limits tumorigenicity.

Purpose To understand the etiology, work-up, and secondary systemic and ocular events of retinal artery occlusion (RAO) in young patients (≤ 45 years old) without typical cardiovascular risk factors. Methods Retrospective longitudinal case series of 18 young patients with RAO and without typical cardiovascular risk factors evaluated at the University of Michigan Medicine Health System between the year 2000 and 2022. Laboratory and imaging studies performed at the time of RAO diagnosis, along with systemic and ocular events during follow-up, were recorded. These data were combined with data from a literature review of 74 similar patients experiencing a RAO. Results Fifteen (83%) of patients were female and 10 (56%) suffered a branch retinal artery occlusion (BRAO). 56% of patients had one risk factor associated with cryptogenic stroke, most commonly a migraine history (33%). The most frequent etiology of RAO was vasculitis (28%), followed by idiopathic (22%) and patent foramen ovale (PFO, 17%). Three out of four patients with idiopathic RAOs developed new migraines around the time of RAO diagnosis, whereas none of the patients with a clear etiology had new onset migraines ( n  = 14). No patients suffered a stroke or myocardial infarction (MI) in the follow-up period (average 3.6 years ± 3.2 years). Two patients (11%) suffered a repeat RAO, both of whom were diagnosed with a vasculitis. Patients with isolated retinal vasculitis required repeat fluorescein angiograms for up to 2 years after the initial event to definitively identify the vasculitic etiology of the RAO. When our data are pooled with similarly healthy patients from previously published RAO series, structural/functional cardiac abnormalities and vasculitides are the most common identifiable etiologies for RAOs in this group. Conclusion The most common identifiable etiologies of RAO in young patients with low cardiovascular risk are structural/functional cardiac abnormalities and vasculitides, with a small range of additional causes/associations accounting for remaining cases. We suggest a focused work-up algorithm to rapidly identify etiologies in this group while minimizing unnecessary testing. The long-term risk of systemic or ocular secondary events in these patients is low regardless of the etiology of their RAO. Key message What was Known: • Retinal artery occlusions (RAOs) in young, healthy individuals are rare, making a data-driven work-up for these patients difficult. What is new: • The most common identifiable etiologies for RAO in young, low cardiovascular risk individuals are functional/structural cardiac abnormalities and vasculitides. • Several repeat fluorescein angiographic studies may be required to diagnose an occult retinal vasculitis. • The long-term risk of secondary systemic or ocular events in young, otherwise healthy individuals is low regardless of the etiology of their RAO.

Summary Bone mineral density is the gold-standard for assessing bone quantity and diagnosing osteoporosis. Although bone mineral density measurements assess the quantity of bone, the quality of the tissue is an important predictor of fragility. Understanding the macro- and nanoscale properties of bone is critical to understanding bone fragility in osteoporosis. Osteoporosis is a disease that affects more than 75 million people worldwide. The gold standard for osteoporosis prognosis, bone mineral density, primarily measures the quantity of bone in the skeleton, overlooking more subtle aspects of bone’s properties. Bone quality, a measure of bone’s architecture, geometry and material properties, is evaluated via mechanical, structural and chemical testing. Although decreased BMD indicates tissue fragility at the clinical level, changes in the substructure of bone can help indicate how bone quality is altered in osteoporosis. Additionally, mechanical properties which can quantify fragility, or bone’s inability to resist fracture, can be changed due to alterations in bone architecture and composition. Recent studies have focused on examination of bone on the nanoscale, suggesting the importance of understanding the interactions of the mineral crystals and collagen fibrils and how they can alter bone quality. It is therefore important to understand alterations in bone that occur at the macro-, micro- and nanoscopic levels to determine what parameters contribute to decreased bone quality in diseased tissue.

The early evidence of domesticated animals and human–animal interaction in South Asia can be traced back to the seventh millennium BCE; however, our understanding of their use is incomplete and limited to the analysis of animal bones from archaeological sites. By the third millennium BCE with the emergence of the Indus Civilization, cattle and water-buffalo became the primary domesticates and outnumbered any other animals at the majority of the Indus settlements. Based on the analysis of skeletal remains and ethnographic data, a number of studies have suggested that cattle and water-buffalo were utilized for their meat, dairy, hides, and other labor-oriented jobs. While some of these claims are backed by empirical data, others are primarily discussed as hypotheses, for example, the exploitation of dairy. In this paper, by analyzing the absorbed lipid residues from fifty-nine ceramic sherds recovered from an agro-pastoral settlement that was occupied during the peak of the Indus period around mid- to late third millennium BCE, we provide the earliest direct evidence of dairy product processing, particularly from cattle and possibly from some water-buffalo. By providing direct evidence of animal product processing, we identify the use of primary domesticated animals and other resources in the diet during the Indus Civilization.

Resonant sensors based on micro- and nano-electro mechanical systems (M/NEMS) are ubiquitous in many sensing applications due to their outstanding performance capabilities, which are directly proportional to the quality factor (Q) of the devices. We address here a recurrent question in the field: do dynamical techniques that modify the effective Q (namely parametric pumping and direct drive velocity feedback) affect the performance of said sensors? We develop analytical models of both cases, while remaining in the linear regime, and introduce noise in the system from two separate sources: thermomechanical and amplifier (read-out) noise. We observe that parametric pumping enhances the quality factor in the amplitude response, but worsens it in the phase response on the resonator. In the case of feedback, we find that Q is enhanced in both cases. Then, we establish a solution for the noisy problem with direct drive and parametric pumping simultaneously. We also find that, in the case when thermomechanical noise dominates, no benefit can be obtained from either artificial Q-enhancement technique. However, in the case when amplifier noise dominates, we surprisingly observe that a significant advantage can only be achieved using parametric pumping in the squeezing region.

In this article, we present a case of optic pit-like macular retinoschisis in the absence of advanced glaucomatous cupping. Intraocular pressure (IOP)-lowering therapy, which was started due to an early concern for glaucoma, caused a worsening of the retinoschisis, which subsequently resolved on discontinuation of the IOP-lowering therapy. Lower IOP likely triggered intraretinal fluid accumulation by facilitating a translaminar gradient from the subarachnoid to intraretinal space. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX–XX.]

Introduction Strontium ranelate (SrR) is suggested to function as a dual-acting agent in the treatment of postmenopausal osteoporosis with anti-resorptive and anabolic skeletal benefits. We evaluated the effects of SrR on the skeleton in ovariectomized (OVX) rats and evaluated the influence of dietary calcium. Methods Three-month old virgin female rats underwent ovariectomy (OVX, n = 50) or SHAM surgery (SHAM, n = 10). Four weeks post-surgery, rats were treated daily by oral gavage with distilled water (10 ml/kg/day) or SrR (25 or 150 mg/kg/day) for 90 days. Separate groups of animals for each dose of SrR were fed a low (0.1%) or normal (1.19%) calcium (Ca) diet. Static and dynamic histomorphometry, DXA, μ-CT, mechanical testing, and serum and skeletal concentrations of strontium were assessed. Results SrR at doses of 25 and 150 mg/kg/day did not increase bone formation on trabecular or periosteal bone surfaces, and failed to inhibit bone resorption of trabecular bone regardless of Ca intake. There were no improvements in bone mass, volume or strength with either dose of SrR given normal Ca. Conclusion These findings demonstrate that SrR at dosages of 25 and 150 mg/kg/day did not stimulate an anabolic bone response, and failed to improve the bone biomechanical properties of OVX rats.

Hard Labor and Hard Time is a history of continuity and change in Florida's state prison system between 1910 and 1957, exploring conditions at the state prison farm at Raiford (the third largest prison farm in the South at this time) as well as in the chain gangs and road prisons. Vivien Miller examines the experiences of the prisoners as well as the guards and other prison personnel in this comprehensive, groundbreaking study. She demonstrates that despite progressive changes in the treatment of inmates (better diet, better structuring of work and leisure activities, better medical provision, and the like), these improvements were matched by continued brutality and mistreatment, unequal or discriminatory treatment according to race and/or gender, and neglect.