Loss of regulation of protein synthesis and turnover underpins an attenuated stress response in senescent human mesenchymal stem cells.

Cells respond to stress by synthesizing chaperone proteins that seek to correct protein misfolding and maintain function. However, abrogation of protein homeostasis is a hallmark of aging, leading to loss of function and the formation of proteotoxic aggregates characteristic of pathology. Consequently, discovering the underlying molecular causes of this deterioration in proteostasis is key to designing effective interventions to disease or to maintaining cell health in regenerative medicine strategies. Here, we examined primary human mesenchymal stem cells, cultured to a point of replicative senescence and subjected to heat shock, as an in vitro model of the aging stress response. Multi -omics analysis showed how homeostasis components were reduced in senescent cells, caused by dysregulation of a functional network of chaperones, thereby limiting proteostatic competence. Time-resolved analysis of the primary response factors, including those regulating heat shock protein 70 kDa (HSPA1A), revealed that regulatory control is essentially translational. Senescent cells have a reduced capacity for chaperone protein translation and misfolded protein (MFP) turnover, driven by downregulation of ribosomal proteins and loss of the E3 ubiquitin ligase CHIP (C-terminus of HSP70 interacting protein) which marks MFPs for degradation. This limits the cell's stress response and subsequent recovery. A kinetic model recapitulated these reduced capacities and predicted an accumulation of MFP, a hypothesis supported by evidence of systematic changes to the proteomic fold state. These results thus establish a specific loss of regulatory capacity at the protein, rather than transcript, level and uncover underlying systematic links between aging and loss of protein homeostasis.

Interactions between climate and COVID-19.

In this Personal View, we explain the ways that climatic risks affect the transmission, perception, response, and lived experience of COVID-19. First, temperature, wind, and humidity influence the transmission of COVID-19 in ways not fully understood, although non-climatic factors appear more important than climatic factors in explaining disease transmission. Second, climatic extremes coinciding with COVID-19 have affected disease exposure, increased susceptibility of people to COVID-19, compromised emergency responses, and reduced health system resilience to multiple stresses. Third, long-term climate change and prepandemic vulnerabilities have increased COVID-19 risk for some populations (eg, marginalised communities). The ways climate and COVID-19 interact vary considerably between and within populations and regions, and are affected by dynamic and complex interactions with underlying socioeconomic, political, demographic, and cultural conditions. These conditions can lead to vulnerability, resilience, transformation, or collapse of health systems, communities, and livelihoods throughout varying timescales. It is important that COVID-19 response and recovery measures consider climatic risks, particularly in locations that are susceptible to climate extremes, through integrated planning that includes public health, disaster preparedness, emergency management, sustainable development, and humanitarian response.

Acellular Dermal Matrix Mimicking a New Retroareolar Mass After Central Pillar Neonipple Reconstruction.

ABSTRACT: Acellular dermal matrix (ADM) is an increasingly popular alloplastic cadaveric dermis used to enhance postmastectomy reconstruction. Acellular dermal matrix can be used as a nipple-shaped cylinder in central pillar nipple reconstruction to help maintain long-term projection. We report a unique presentation of ADM mimicking a retroareolar mass after central pillar neonipple reconstruction. A 49-year-old woman with a history of invasive ductal carcinoma underwent delayed nipple reconstruction after lumpectomy and oncoplastic closure using an inframammary V-Y advancement flap.The nipple reconstruction was performed using pretattoo and articulated tab flaps. A rolled tube of acellular dermal matrix was placed in the central aspect of the neonipple reconstruction for projection. At 4 months postoperative, a screening mammogram and ultrasound noted a new retroareolar mass classified as BIRADS 4 necessitating a breast biopsy. Biopsy revealed portions of fibrous connective tissue consistent with partially incorporated acellular dermal matrix allograft. There was no evidence of malignancy. To mitigate the risk of future radiographic or clinical misinterpretation of ADM in nipple reconstruction, the placement of radiopaque markers such as microclips on the ADM implant could be a useful adjunct. Radiologists and surgeons should include ADM artifact in their differential diagnosis of radiologic imaging when evaluating a new mass in the proximity of prior ADM placement in neonipple reconstruction of the breast.

Correction: Single nucleotide polymorphisms in the human ATP7B gene modify the properties of the ATP7B protein.

Correction for 'Single nucleotide polymorphisms in the human ATP7B gene modify the properties of the ATP7B protein' by Courtney J. McCann et al., Metallomics, 2019, 11, 1128-1139.

Single nucleotide polymorphisms in the human ATP7B gene modify the properties of the ATP7B protein.

Single nucleotide polymorphisms (SNPs) are the largest source of sequence variation in the human genome. However, their functional significance is not well understood. We show that SNPs in the Wilson disease gene, ATP7B, that produce amino-acid substitutions K832R and R952K, modulate ATP7B properties in vitro and influence serum copper (Cu) status in vivo. The presence of R832 is associated with a lower ATP7B abundance and a diminished trafficking in response to elevated Cu. The K832R substitution alters surface exposure of amino acid residues in the actuator domain and increases its conformational flexibility. All SNP-related ATP7B variants (R832/R952, R832/K952, K832/K952, and K832/R952) have Cu-transport activity. However, the activity of ATP7B-K832/K952 is lower compared to other variants. In humans, the presence of K952 is associated with a higher fraction of exchangeable Cu in serum. Thus, SNPs may modulate the properties of ATP7B and the organism Cu status.

Initiation of spontaneous tumors in radish (Raphanus sativus): Cellular, molecular and physiological events.

In plant meristems, the balance of cell proliferation and differentiation is maintained by phytohormones, specifically auxin and cytokinin, as well as transcription factors. Changing of the cytokinin/auxin balance in plants may lead to developmental abnormalities, and in particular, to the formation of tumors. The examples of spontaneous tumor formation in plants include tumors formed on the roots of radish (Raphanus sativus) inbred lines. Previously, it was found that the cytokinin/auxin ratio is altered in radish tumors. In this study, a detailed histological analysis of spontaneous radish tumors was performed, revealing a possible mechanism of tumor formation, namely abnormal cambial activity. The analysis of cell proliferation patterns revealed meristematic foci in radish tumors. By using a fusion of an auxin-responsive promoter (DR5) and a reporter gene, the involvement of auxin in developmental processes in tumors was shown. In addition, the expression of the root meristem-specific WUSCHEL-related homeobox 5 (WOX5) gene was observed in cells adjacent to meristematic foci. Taken together, the results of the present study show that tumor tissues share some characteristics with root apical meristems, including the presence of auxin-response maxima in meristematic foci with adjacent cells expressing WOX5.

Renal artery aneurysm in robotic donor nephrectomy: a case report.

OBJECTIVES: With the current disparity between donor organ availability and recipient need, creative techniques help optimize the use of available organs. We present a case of a woman, who was worked-up as a kidney donor, who was incidentally found to have a saccular aneurysm on her renal artery. The patient was asymptomatic, normotensive, and had normal renal function. MATERIALS AND METHODS: We performed a laparoscopic robotic donor nephrectomy, repaired the aneurysm on the back table, and transplanted the organ into the recipient. RESULTS: The donor underwent a successful robotic nephrectomy, successfully eradicating any risk of aneurysmal complications; the recipient received an anatomically normal organ with excellent function. CONCLUSIONS: An altruistic act by the donor identified a potentially fatal lesion, which was not only remedied, but the intended donation proceeded when a creative approach was used.

Wuschel-related homeobox5 gene expression and interaction of CLE peptides with components of the systemic control add two pieces to the puzzle of autoregulation of nodulation.

In legumes, the symbiotic nodules are formed as a result of dedifferentiation and reactivation of cortical root cells. A shoot-acting receptor complex, similar to the Arabidopsis (Arabidopsis thaliana) CLAVATA1 (CLV1)/CLV2 receptor, regulating development of the shoot apical meristem, is involved in autoregulation of nodulation (AON), a mechanism that systemically controls nodule number. The targets of CLV1/CLV2 in the shoot apical meristem, the WUSCHEL (WUS)-RELATED HOMEOBOX (WOX) family transcription factors, have been proposed to be important regulators of apical meristem maintenance and to be expressed in apical meristem "organizers." Here, we focus on the role of the WOX5 transcription factor upon nodulation in Medicago truncatula and pea (Pisum sativum) that form indeterminate nodules. Analysis of temporal WOX5 expression during nodulation with quantitative reverse transcription-polymerase chain reaction and promoter-reporter fusion revealed that the WOX5 gene was expressed during nodule organogenesis, suggesting that WOX genes are common regulators of cell proliferation in different systems. Furthermore, in nodules of supernodulating mutants, defective in AON, WOX5 expression was higher than that in wild-type nodules. Hence, a conserved WUS/WOX-CLV regulatory system might control cell proliferation and differentiation not only in the root and shoot apical meristems but also in nodule meristems. In addition, the link between nodule-derived CLE peptides activating AON in different legumes and components of the AON system was investigated. We demonstrate that the identified AON component, NODULATION3 of pea, might act downstream from or beside the CLE peptides during AON.

Crystal nucleation, growth, and morphology of the synthetic malaria pigment beta-hematin and the effect thereon by quinoline additives: the malaria pigment as a target of various antimalarial drugs.

The morphology of micrometer-sized beta-hematin crystals (synthetic malaria pigment) was determined by TEM images and diffraction, and by grazing incidence synchrotron X-ray diffraction at the air-water interface. The needle-like crystals are bounded by sharp {100} and {010} side faces, and capped by {011} and, to a lesser extent, by {001} end faces, in agreement with hemozoin (malaria pigment) crystals. The beta-hematin crystals grown in the presence of 10% chloroquine or quinine took appreciably longer to precipitate and tended to be symmetrically tapered toward both ends of the needle, due to stereoselective additive binding to {001} or {011} ledges. Evidence, but marginal, is presented that additives reduce crystal mosaic domain size along the needle axis, based on X-ray powder diffraction data. Coherent grazing exit X-ray diffraction suggests that the mosaic domains are smaller and less structurally stable than in pure crystals. IR-ATR and Raman spectra indicate molecular based differences due to a modification of surface and bulk propionic acid groups, following additive binding and a molecular rearrangement in the environment of the bulk sites poisoned by occluded quinoline. These results provided incentive to examine computationally whether hemozoin may be a target of antimalarial drugs diethylamino-alkoxyxanthones and artemisinin. A variation in activity of the former as a function of the alkoxy chain length is correlated with computed binding energy to {001} and {011} faces of beta-hematin. A model is proposed for artemisinin activity involving hemozoin nucleation inhibition via artemisinin-beta-hematin adducts bound to the principal crystal faces. Regarding nucleation of hemozoin inside the digestive vacuole of the malaria parasite, nucleation via the vacuole's membranous surface is proposed, based on a reported hemozoin alignment. As a test, a dibehenoyl-phosphatidylcholine monolayer transferred onto OTS-Si wafer nucleated far more beta-hematin crystals, albeit randomly oriented, than a reference OTS-Si.