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The purse-string DIEPplasty technique is a method to improve aesthetic outcomes in breast reconstruction using deep inferior epigastric perforator (DIEP) free flaps. Traditionally, DIEP flaps, harvested from the lower abdomen, take on a triangular shape that can lead to sub-optimal aesthetic outcomes with occasionally poor breast projection, irregular contours, or minimal upper pole fullness. The purse-string DIEPplasty technique addresses these issues by using a 0 Polydioxanone continuous purse-string suture through the Scarpa’s fascia to modify the harvested flap’s shape before inset, giving it a more round base and a central dome-like projection similar to an implant. This method mimics the shape of a breast implant, enhancing the flap's projection, volumetric efficiency, and overall shape, leading to a reconstructed breast with improved aesthetic qualities. This technique represents a potential advancement in reconstructive breast surgery, aiming to reduce the extent of revision procedures and improve patient satisfaction. Further research, however, is needed to validate its effectiveness over time and assess potential complications. Level of Evidence IV This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

A variant of the toll-like receptor 3 (TLR3) provides protection against geographic atrophy, or “dry” age-related macular degeneration, and reduces apoptosis of cultured retinal pigment epithelial cells on exposure to TLR3 ligand. Because double-stranded RNA is a ligand of TLR3, this finding gives rise to the hypothesis that viral infection causes this disease and to concerns about therapeutic intraocular injection of short interfering RNA. A variant of the toll-like receptor 3 (TLR3) provides protection against geographic atrophy, or “dry” age-related macular degeneration, and reduces apoptosis of cultured retinal pigment epithelial cells on exposure to TLR3 ligand. Age-related macular degeneration is the leading cause of irreversible blindness in the developed world. The disease is broadly classified according to its severity and likelihood of progression. The hallmark of the condition is the presence of drusen, or deposits in the macula (central retina). When the drusen are confluent and “soft” in appearance, the affected person is considered to have early-to-intermediate age-related macular degeneration, even though vision is usually unaffected. The greater the number and size of the drusen, the greater the risk of progression to either form of advanced age-related macular degeneration: extensive atrophy of the retinal pigment epithelium . . .

Significant morbidity and mortality among patients with diabetes mellitus result largely from a greatly increased incidence of microvascular complications. Proliferative diabetic retinopathy (PDR) and end stage renal disease (ESRD) are two of the most common and severe microvascular complications of diabetes. A high concordance exists in the development of PDR and ESRD in diabetic patients, as well as strong familial aggregation of these complications, suggesting a common underlying genetic mechanism. However, the precise gene(s) and genetic variant(s) involved remain largely unknown. Erythropoietin (EPO) is a potent angiogenic factor observed in the diabetic human and mouse eye. By a combination of case-control association and functional studies, we demonstrate that the T allele of SNP rs1617640 in the promoter of the EPO gene is significantly associated with PDR and ESRD in three European-American cohorts [Utah: P = 1.91 x 10⁻³; Genetics of Kidneys in Diabetes (GoKinD) Study: P = 2.66 x 10⁻⁸; and Boston: P = 2.1 x 10⁻²]. The EPO concentration in human vitreous body was 7.5-fold higher in normal subjects with the TT risk genotype than in those with the GG genotype. Computational analysis suggests that the risk allele (T) of rs1617640 creates a matrix match with the EVI1/MEL1 or AP1 binding site, accounting for an observed 25-fold enhancement of luciferase reporter expression as compared with the G allele. These results suggest that rs1617640 in the EPO promoter is significantly associated with PDR and ESRD. This study identifies a disease risk-associated gene and potential pathway mediating severe diabetic microvascular complications.

A common haplotype on 10q26 influences the risk of age-related macular degeneration (AMD) and encompasses two genes, LOC387715 and HTRA1. Recent data have suggested that loss of LOC387715, mediated by an insertion/deletion (in/del) that destabilizes its message, is causally related with the disorder. Here we show that loss of LOC387715 is insufficient to explain AMD susceptibility, since a nonsense mutation (R38X) in this gene that leads to loss of its message resides in a protective haplotype. At the same time, the common disease haplotype tagged by the in/del and rs11200638 has an effect on the transcriptional upregulation of the adjacent gene, HTRA1. These data implicate increased HTRA1 expression in the pathogenesis of AMD and highlight the importance of exploring multiple functional consequences of alleles in haplotypes that confer susceptibility to complex traits.

UNC119 is a protein localized to the non-motile primary cilia. Here, Zhang et al . report the crystal structure of UNC119 and provide biochemical and cellular evidence that UNC119 is a lipid-binding protein that mediates G protein trafficking. The authors also show that that UNC119 function is conserved from GPCR trafficking in C. elegans olfactory neuron to transducin trafficking in mammalian photoreceptors. UNC119 is widely expressed among vertebrates and other phyla. We found that UNC119 recognized the acylated N terminus of the rod photoreceptor transducin α (Tα) subunit and Caenorhabditis elegans G proteins ODR-3 and GPA-13. The crystal structure of human UNC119 at 1.95-Å resolution revealed an immunoglobulin-like β-sandwich fold. Pulldowns and isothermal titration calorimetry revealed a tight interaction between UNC119 and acylated Gα peptides. The structure of co-crystals of UNC119 with an acylated Tα N-terminal peptide at 2.0 Å revealed that the lipid chain is buried deeply into UNC119′s hydrophobic cavity. UNC119 bound Tα-GTP, inhibiting its GTPase activity, thereby providing a stable UNC119–Tα-GTP complex capable of diffusing from the inner segment back to the outer segment after light-induced translocation. UNC119 deletion in both mouse and C. elegans led to G protein mislocalization. Thus, UNC119 is a Gα subunit cofactor essential for G protein trafficking in sensory cilia.

The mammalian photoreceptor is a dynamic polarized cell, in which protein transport and translocation are continuously taking place. The ability of these cells to accurately and efficiently localize protein components is essential for survival and proper functioning. Post-biosynthesis protein transport from IS to OS and translocation of transducin from OS to IS and back again, in response to light and dark, respectively, test the transport systems in these cells. Additionally, localization of membrane-associated proteins offers a challenge, as lipidated proteins must move freely within the hydrophilic intracellular environment until reaching a destination membrane. As a result, photoreceptors are an ideal model for studying intracellular membrane-associated protein trafficking. Chapter 1 reviews photoreceptor structure and describes the need for accurate and efficient transport mechanisms in these cells. Eukaryotic prenylation and acylation are examined providing context for discussing the biosynthesis, transport, and light-induced translocation of transducin. Lastly, UNC119, which interacts with and is critical in mediating transducin's translocation, is reviewed. Chapter 2 focuses on the biochemical and structural characterization of the UNC119-transducin-α interaction. The co-crystal structure of UNC119-Lauroyl-GAGASAEEKH at 2.0Å resolution offers definitive evidence for this interaction. Wild-type and Unc119-/- mouse models in conjunction with C. elegans unc-119 mutants provide in vivo evidence that UNC119 is required for G protein trafficking in sensory neurons. These data provide the first detailed description of a specific UNC119 function offering insight into the mechanism underlying transducin light-induced translocation. Chapter 3 touches on the generation of an UNC119-Tα-GMP·PNP complex, but moves away from light-induced translocation and describes the role PrBP/δ plays in post-biosynthesis transport of PDE6. A general review of PrBP/δ and PDE6 offers a basic foundation for understanding how these two proteins interact and what role this interaction plays. While efforts focused on generating protein crystals of a PrBP/δ-PDE6 complex were unsuccessful, collaboration with Ted Wensel's group yielded a cryo-EM reconstruction of the complex and its features and implications are discussed. Chapter 4 concludes this work with discussions of the aforementioned findings and future directions that might prove useful in further understanding the role UNC119 plays in G protein trafficking and how the PDE6-PrBP/δ complex assembles.

A common haplotype on 10q26 influences the risk of age-related macular degeneration (AMD) and encompasses two genes, LOC387715 and HTRA1. Recent data have suggested that loss of LOC387715, mediated by an insertion/deletion (in/del) that destabilizes its message, is causally related with the disorder. Here we show that loss of LOC387715 is insufficient to explain AMD susceptibility, since a nonsense mutation (R38X) in this gene that leads to loss of its message resides in a protective haplotype. At the same time, the common disease haplotype tagged by the in/del and rs11200638 has an effect on the transcriptional upregulation of the adjacent gene, HTRA1. These data implicate increased HTRA1 expression in the pathogenesis of AMD and highlight the importance of exploring multiple functional consequences of alleles in haplotypes that confer susceptibility to complex traits.

More people are presenting with mild cognitive impairment (MCI), frequently a precursor to dementia, but we do not know how to reduce deterioration. To systematically review randomised controlled trials (RCTs) evaluating the effects of any intervention for MCI on cognitive, neuropsychiatric, functional, global outcomes, life quality or incident dementia. We reviewed 41 studies fitting predetermined criteria, assessed validity using a checklist, calculated standardised outcomes and prioritised primary outcome findings in placebo-controlled studies. The strongest evidence was that cholinesterase inhibitors did not reduce incident dementia. Cognition improved in single trials of: a heterogeneous psychological group intervention over 6 months; piribedil, a dopamine agonist over 3 months; and donepezil over 48 weeks. Nicotine improved attention over 6 months. There was equivocal evidence that Huannao Yicong improved cognition and social functioning. There was no replicated evidence that any intervention was effective. Cholinesterase inhibitors and rofecoxib are ineffective in preventing dementia. Further good-quality RCTs are needed and preliminary evidence suggests these should include trials of psychological group interventions and piribedil.

The efficiency of the synthesis of renewable fuels and feedstocks from electrical sources is limited, at present, by the sluggish water oxidation reaction. Single-atom catalysts (SACs) with a controllable coordination environment and exceptional atom utilization efficiency open new paradigms toward designing high-performance water oxidation catalysts. Here, using operando X-ray absorption spectroscopy measurements with calculations of spectra and electrochemical activity, we demonstrate that the origin of water oxidation activity of IrNiFe SACs is the presence of highly oxidized Ir single atom (Ir5.3+) in the NiFe oxyhydroxide under operating conditions. We show that the optimal water oxidation catalyst could be achieved by systematically increasing the oxidation state and modulating the coordination environment of the Ir active sites anchored atop the NiFe oxyhydroxide layers. Based on the proposed mechanism, we have successfully anchored Ir single-atom sites on NiFe oxyhydroxides (Ir0.1/Ni₉Fe SAC) via a unique in situ cryogenic–photochemical reduction method that delivers an overpotential of 183 mV at 10 mA · cm−2 and retains its performance following 100 h of operation in 1 M KOH electrolyte, outperforming the reported catalysts and the commercial IrO₂ catalysts. These findings open the avenue toward an atomic-level understanding of the oxygen evolution of catalytic centers under in operando conditions.

Background Despite controversies, epinephrine remains a mainstay of cardiopulmonary resuscitation (CPR). Recent animal studies have suggested that epinephrine may decrease cerebral blood flow (CBF) and cerebral oxygenation, possibly potentiating neurological injury during CPR. We investigated the cerebrovascular effects of intravenous epinephrine in a swine model of pediatric in-hospital cardiac arrest. The primary objectives of this study were to determine if (1) epinephrine doses have a significant acute effect on CBF and cerebral tissue oxygenation during CPR and (2) if the effect of each subsequent dose of epinephrine differs significantly from that of the first. Methods One-month-old piglets ( n  = 20) underwent asphyxia for 7 min, ventricular fibrillation, and CPR for 10–20 min. Epinephrine (20 mcg/kg) was administered at 2, 6, 10, 14, and 18 min of CPR. Invasive (laser Doppler, brain tissue oxygen tension [PbtO 2 ]) and noninvasive (diffuse correlation spectroscopy and diffuse optical spectroscopy) measurements of CBF and cerebral tissue oxygenation were simultaneously recorded. Effects of subsequent epinephrine doses were compared to the first. Results With the first epinephrine dose during CPR, CBF and cerebral tissue oxygenation increased by > 10%, as measured by each of the invasive and noninvasive measures ( p  < 0.001). The effects of epinephrine on CBF and cerebral tissue oxygenation decreased with subsequent doses. By the fifth dose of epinephrine, there were no demonstrable increases in CBF of cerebral tissue oxygenation. Invasive and noninvasive CBF measurements were highly correlated during asphyxia (slope effect 1.3, p  < 0.001) and CPR (slope effect 0.20, p  < 0.001). Conclusions This model suggests that epinephrine increases CBF and cerebral tissue oxygenation, but that effects wane following the third dose. Noninvasive measurements of neurological health parameters hold promise for developing and directing resuscitation strategies.