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Translational research describes the process of converting basic scientific findings into novel treatments and diagnostics aimed to address unmet clinical needs. Here, we showcase a plethora of diverse studies, ranging from the investigation of the molecular mechanisms underlying the onset and course of a disease using preclinical models, to the development of innovative interventions in human subjects with the goal to guide health care policy and clinical practice.
Manual processes to produce ocular prostheses are time-consuming and yield varying quality. Here, authors present an automatic digital end-to-end process for custom ocular prostheses. It creates shape and appearance from image data of an OCT device and produces them using a full-colour 3D printer.
The acid–base balance regulates cellular responses, but little has been known about its molecular mechanism. Here, the authors unveil a bicarbonate-sensing GPCR, GPR30, that underlies cerebral ischemia–reperfusion injury by regulating blood flow recovery.
Epidemiological evidence has identified associations among obesity, Alzheimer’s disease, and cardiovascular disease. Here, the authors report that adipose tissue releases amyloid beta 42 (Aβ42) and that antagonizing Aβ42 protects cardiac function in obesity murine models.
Hepatocytes regenerate the liver after injury, however, the tissue repair mechanisms have been little explored. Here, the authors show that midlobular and pericentral hepatocytes increase their number and size in response to chemical, physical, and viral insults facilitating liver regeneration.
Overfeeding triggers a mechanistically ill-defined compensatory response that counteracts weight gain. Here, the authors show that the defence against overfeeding is preserved in obesity, and that it is independent from FGF21 and MC4R.
Surgery poses significant risks for patients, with attempts to mitigate these risks using multimodal perioperative care pathways. Here, the authors show that preoperative hypercaloric carbohydrate drinks not only alleviate surgical stress but also demonstrates the replicability of this protection using FGF21 treatment alone.
In vivo detection of cell senescence remains a challenge in aging research. This work introduces a novel fluorogenic probe for β-Gal activity that is excreted in urine, providing a simple diagnosis method to estimate the systemic load of senescent cells during aging and senolytic interventions.
Using different mouse models of Polycystic Kidney Disease, this research demonstrated that deletion of the Aurora Kinase A gene was able to prevent cyst initiation and growth, identifying it as a central regulator of pathogenesis in this condition.
A personalized letter from the Medical Examiner-Coroner in Los Angeles County has proven effective at reducing opioid and benzodiazepine prescribing. Here the authors show that the introduction of if/when-then planning prompts in to the letter further reduced opioid prescribing by 12.85% and benzodiazepine prescribing by 8.32%; they were most effective for clinicians with multiple patient deaths due to accidental opioid-related overdose.
This study uncovers a critical link between DNMT3A-driven CHIP and heart failure and, in particular, it shows that DNMT3A inactivation in monocytes boosts the release of HB-EGF, which activates fibroblasts inducing diffuse fibrosis in the heart.
MyoD is a transcription factor expressed in skeletal muscle that plays a critical role in determining myogenic cell fate. Here, Hu et al. reveal a metabolic role of MyoD in orchestrating systemic energy homeostasis by mediating muscle-fat crosstalk through the muscle-secreted lipokine DLPC.
Ameliorating or preventing signatures of aging in humans using natural compounds is an exciting area of research. Here the authors isolate a previously unknown phytochemical from carrots which activates defence mechanisms against oxidative stress and extends lifespan in worms, and improves glucose metabolism, promotes exercise capacity, and protects from frailty at higher age in mice.
Mazdutide is a once-weekly glucagon-like peptide-1 (GLP-1) and glucagon receptor dual agonist. Here, the authors show mazdutide was well tolerated over 24 weeks and demonstrated significant and clinically meaningful body weight loss, compared with placebo, in Chinese overweight adults or adults with obesity.
Catecholaminergic transmitters are critical signalling effectors known to be released by sympathetic nerves and adrenomedullary endocrine cells in response to physiological stress. In this paper, the authors demonstrate a uniquely distributed group of catecholaminergic cardiomyocytes with key regulatory roles in cardiac excitation conduction.
In patients with CKD, there is an unmet need for biomarkers that reliably track kidney injury. Here, in a series of prospective studies, the authors show that retinal OCT metrics reflect kidney injury, are modified by treatments for kidney disease and can predict future decline of kidney function.
Fentanyl continues to drive the opioid crisis by contributing to >70,000 deaths per year in the US. Here, the authors investigate a candidate medication for fentanyl overdose prevention (monoclonal antibody CSX-1004) demonstrating its mitigation of fentanyl’s effects in preclinical animal models.
A PET tracer for α-synuclein would help diagnosis and treatment of α-syn-related diseases. Here the authors show that ACI-12589 shows an uptake in the cerebellar white matter in patients with multiple-system atrophy.
It is unknown whether unrepaired DNA damage in lung endothelial cells causes persistent pulmonary arterial hypertension. Here, the authors combine oxidative stress with impaired BMPR2 signaling to link a reduction in FOXF1 to unrepaired DNA damage and impaired regeneration of normal endothelium.
The authors report data from a Phase IIa randomised, double-blind trial in patients with NASH showing that BI 1467335 strongly and dose-dependently inhibited AOC3 activity (involved in hepatic inflammation) and was well tolerated at all tested doses.
Here, authors report chemokine receptors structures obtained using coarse-grained metadynamics. CCR5 and CXCR4 homo- and heterodimers differ in the conformations of ligand binding sites and of the G protein interaction interface, suggesting structural basis for the rational design of biased ligands.
Fibrocystin/Polyductin (FPC) is a large ciliary membrane protein encoded by PKHD1 which, when mutated, causes ARPKD. Here, the authors show that FPC suppresses cyst development in the kidney of mouse models through the release and mitochondrial translocation of its C terminal product.
Non-alcoholic fatty liver disease is a growing health burden with limited treatment options worldwide. Herein the authors report a randomized, double-blind, placebo-controlled, multiple-dose trial of a first-in-class pan-phosphodiesterase inhibitor ZSP1601 in NAFLD patients.
Genotype patterns may modify diet effects on weight loss, with greater weight loss on genotype-concordant diets. Here, the authors show that with the current ability to genotype participants as fat- or carbohydrate-responders, evidence does not support greater weight loss on genotype-concordant diets.
β-cell dysfunction in type 2 diabetes is associated with pathological aggregates of IAPP that accumulate in pancreatic islets. Here, the authors describe a novel antibody cloned from healthy elderly donors that selectively targets IAPP oligomers and protects from IAPP toxicity.
β-thalassemia is a prevalent genetic disorder causing severe anemia, with study of the underlying molecular defects impeded by paucity of suitable patient material. Here, the authors show that cellular model systems of βthalassemia can be used to identify new therapeutic targets and as screening platforms for new drugs and reagents.
A common East Asian-specific defect of an alcohol metabolizing enzyme (ALDH2) causes glucose abnormality, obesity, and fatty liver. Here, the authors show an ALDH2 activator can treat these metabolic disorders in mice.
Long-term machine perfusion of human livers outside the body is an emerging field with tremendous potential for the assessment, recovery, and modification of organs prior to transplantation. Here, the authors report the long-term ex situ perfusion of human livers and demonstrate the ability to split and perfuse these organs using a standardised protocol.
Muscle stem cells drive muscle regeneration and are affected in myotonic dystrophy type 1. Here, the authors demonstrate that some muscle stem cells show signs of senescence in myotonic dystrophy type 1 and administer senolytics to eliminate these defective cells and restore myogenesis.
In early type 2 diabetes, “induction” with short-term insulin therapy followed by “maintenance” with metformin can stabilize beta-cell function. The authors show that initial reversibility of beta-cell dysfunction followed by preserved hepatic insulin sensitivity determine sustained stabilization.
The mechanisms of failed tubule repair after acute kidney injury are incompletely understood. Here, the authors show spatial and temporal analysis of cycling cells relative to initial necrosis and postulate pronounced injury expansion into non-necrotic tissue regions, predictive of tubule atrophy.
Chemotherapy can cause severe damage to cardiomyocytes in some patients but it is unclear how cardiomyocytes protect themselves against such stress. Here the authors show that cardiomyocytes initiate an endogenous protective response when exposed to chemotherapeutic agents by translocating mitochondrial enzymes to the nucleus.
Proteinuric kidney diseases are on the rise and have limited treatment options. Here, the authors show soluble urokinase receptor (suPAR) orchestrates viral response proteinuria (VRP) which occurs in response to certain viral infections and podocyte integrin engagement.
Macrophages are increasingly recognized as key drivers of lung damage in acute pneumonia including COVID-19. Here, the authors report on a first-in-class, inhalable, carbohydrate-coupled microRNA-inhibitor for selective targeting of macrophages and that prevents pulmonary hyperinflammation.
Current clinical methods for assessing kidney function report an aggregate value for both kidneys, and lack the ability to say which kidney is dysfunctioning or even to localize the dysfunction to a region of renal pathology. Here, the authors show that an injectable dye can be used to map kidney function by magnetic resonance imaging, offering a safer alternative than existing dyes for the spatial evaluation of kidney health.
Cellular senescence is involved in many disease processes but few senolytic compounds are currently known. Here, the authors report the discovery of three senolytics using machine learning models trained solely on published data, with large reductions in drug screening costs.
The PAH P281L variant is one of the most common variants identified in phenylketonuria (PKU) patients. Here, the authors use base editing, enabled by lipid nanoparticle/mRNA technology, to directly correct the P281L variant in the liver in PKU mice and definitively treat the disease within 2 days.
Beige adipocytes quickly transition into white adipocytes upon the removal of stimuli, limiting their therapeutic potential for chronic metabolic diseases. In this study, the authors show that inhibiting Cdkn2a-Becn1 mediated autophagy can maintain beige adipocytes and provide long term metabolic health benefits in mice.
The association between primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) has been known for decades, but mechanisms of gut-liver crosstalk are incompletely understood. Here, the authors show a colitis-triggered protective circuit suppressing cholestatic liver disease which encourages multi-organ treatment strategies for PSC.
Authors present both preclinical data in mice and clinical data from humans in support of the hypothesis that stress negatively affects bone growth and repair. These effects are mediated by neutrophil-derived catecholamines inhibiting cartilage-to-bone transition via β2-adrenoceptor signaling in chondrocytes.
This study demonstrates the safety and long-term efficacy of a single-dose, injectable contraceptive in female domestic cats. Treated females remained contracepted for over two years, and did not ovulate or produce kittens when paired with males.
Mutations in the RRAGD gene are causative of an autosomal dominant disorder characterized by kidney tubulopathy and cardiomyopathy. Here, the authors identify a new RRAGD P88L mutation, demonstrating that all the identified RRAGD mutations inhibit the nuclear translocation of MiT/TFE transcription factors, resulting in defective responses to lysosomal or mitochondrial damage.
We know that nutrition and obesity can impact male fertility, but specific dietary guidelines for men trying to conceive don’t exist. Here the authors show that diet composition is likely more important than body fat in influencing reproductive traits and each macronutrient has different impacts.
Antiplatelet medication is standard care in myocardial infarction (MI). Here, the authors show that platelets release bioactive sphingosine-1- phosphate (S1P) during MI to protect the heart against injury, and that certain antiplatelet drugs preserve this favourable S1P release, while others don’t.
Mutations in the gene encoding PC1 cause ADPKD, a common genetic renal disease. Here, the authors show that expression of the C-terminal 200 amino acids of the large PC1 protein in mouse models of ADPKD suppresses cystic disease through an interaction with the mitochondrial enzyme NNT.
This study characterizes expression of pharmacogenes across the histological NAFLD severity spectrum. Here, the authors show the downregulation of CYP2C19 in NAFLD which supports developing personalized medicine approaches for drugs sensitive to metabolism by the CYP2C19 enzyme.
Neutrophilic inflammation is a hallmark of many monogenic autoinflammatory diseases. Here the authors report a case series of three unrelated boys with perinatal-onset of neutrophilic cutaneous small vessel vasculitis and systemic inflammation, and identify de novo truncating and missense variants in the Src-family tyrosine kinase LYN.
Dorzagliatin, which acts on the glucose sensor glucokinase, is a new class of anti-diabetic medicine. Here the authors report that in a phase I open-label trial co-administration of dorzagliatin and sitagliptin (a different class of anti-diabetic medicine) does not significantly change the pharmacokinetics of either medicine in patients with type 2 diabetes and obesity.
Here, the authors identify a novel regulator of autophagy, skeletal muscle mass and integrity named MYTHO. Silencing MYTHO protects against muscle atrophy in a wide range of acute catabolic conditions, while prolonged silencing causes a severe myopathy.
Activation of breathing during hypoxia is abolished in mice lacking mitochondrial complex I in carotid body chemoreceptors, however the specific contribution of mitochondrial complex I to this process is unclear. Here, the authors show that recovery of NADH dehydrogenase activity, but not proton pumping, by transgenic expression of a yeast enzyme rescues cellular and systemic sensitivity to changes in O2 tension.