Optimizing inorganic carbon and salinity for enhanced biomass and pigment production in Colaconema formosanum: Implications for sustainable carbon sequestration and stress responses.

This study investigates a cultivation strategy for the macroalga Colaconema formosanum by determining optimal inorganic carbon concentration and salinity for maximizing biomass and photosynthetic pigment production while also facilitating carbon sequestration. The response surface method was used with a central composite design (CCD-RSM) to determine the optimal conditions. Results showed that adding 1.2 g/L of carbon increased the specific growth rate to 18%-19% per day. The maximum amount of pigment, including phycobiliprotein and chlorophyll, was achieved by adjusting both carbon content and salinity. This strategy enables mass pigment production and offers an eco-friendly approach to carbon sequestration while reducing culture period. This study also sheds light on algal mechanisms against enriched inorganic carbon and salinity content, contributing to an enhanced understanding of these vital processes.

Genomic and tumour microenvironmental biomarkers of immune checkpoint inhibitor response in advanced Taiwanese melanoma.

Objective: Genomic biomarkers predicting immune checkpoint inhibitor (ICI) treatment outcomes for Asian metastatic melanoma have been rarely reported. This study presents data on next-generation sequencing (NGS) and tumour microenvironment biomarkers in 33 cases. Methods: Thirty-three patients with advanced melanoma, who underwent ICI treatment at the Chang Gung Memorial Hospital in Taiwan, were recruited. The study evaluated clinical outcomes, including response rate, disease control rate, progression-free survival (PFS) rate and overall survival (OS) rate. Archived tissue samples from 33 cases were subjected to NGS by ACTOnco, and ACTTME was employed in 25 cases. Results: The most prevalent driver mutations were BRAF mutations (24.2%), followed by NRAS (15.2%), KIT (12.1%), KRAS (9.1%) and NF1 (9.1%) mutations. Acral/mucosal melanomas exhibited distinct mutation patterns compared to non-acral melanomas. Tumour mutational burden estimated using ACTOnco was not associated with ICI efficacy. Notably, genetic alterations in the p53 pathway (CDKNA2 loss, MDM2 gain/amplification and TP53 mutation) accounted for 36.4% and were significantly associated with unfavourable PFS (median PFS 2.7 months vs. 3.9 months, P = 0.0394). Moreover, 26 genes were identified as differentially expressed genes that were upregulated in patients with clinical benefits compared to those without benefits. Four genes, GZMH, GZMK, AIM2 and CTLA4, were found to be associated with both PFS and OS. Conclusion: Genetic alterations in the p53 pathway may be critical in Asian patients with melanoma undergoing ICI treatment. Further investigation is required to explore this mechanism and validate these findings.

Association of Glaucoma with the Risk of Peripheral Arterial Occlusive Disease: A Retrospective Population-Based Cohort Study.

This study aimed to investigate the potential association between glaucoma and peripheral arterial occlusive disease. The study recruited patients, including 101,309 with glaucoma and 1,860,528 without a glaucoma diagnosis, from a population of 2 million patients in the Longitudinal Health Insurance Database. Propensity score matching was performed between the two groups, matching for age, sex, and comorbidities. In total, 95,575 patients with glaucoma and 95,575 patients without glaucoma were analyzed for their risk of developing peripheral arterial occlusive disease. The analysis of the data revealed that the glaucoma group had a higher incidence density (ID = 4.13) of peripheral arterial occlusive disease than the non-glaucoma group (ID = 3.42). The relative risk for the glaucoma group was 1.21 (95% C.I. = 1.15-1.28). Cox proportional hazard model analysis indicated that the glaucoma group had a higher risk of developing peripheral arterial occlusive disease (HR = 1.18; 95% C.I. = 1.12-1.25). The subgroup analysis of the risk of PAOD showed that the glaucoma group had a higher risk of developing peripheral arterial occlusive disease in the age group of 20 to 39 (p for interaction = 0.002). In conclusion, patients with glaucoma were associated with a higher risk of subsequent peripheral arterial occlusive disease compared with those without a diagnosis of glaucoma.

Comparison of suture-bridge and independent double-row techniques for medium to massive posterosuperior cuff tears: a two-year retrospective study.

BACKGROUND: Transosseous-equivalent suture-bridge (TOE-SB) and independent double-row (IDR) repair techniques were developed to treat rotator cuff tears. The study was designed to prove that both TOE-SB and IDR techniques provided comparable clinical results and retear rate for medium to massive posterosuperior rotator cuff tears, while the surgical time and number of suture anchor used were less in the IDR group. STUDY DESIGN: Level of evidence: level III, Retrospective comparative study. METHODS: Patients with medium to massive posterosuperior rotator cuff tears receiving arthroscopic TOE-SB and IDR between November 2016 to October 2019 were retrospectively enrolled. All patients were confirmed to have grade ≤ 2 fatty infiltration in the muscles of the torn tendons. Revision, concomitant subscapularis tear, acromiohumeral distance < 7 mm, glenohumeral osteoarthritis, partial repair, incomplete repair, partial thickness, or irreparable posterosuperior cuff tear were excluded. Surgical time, number of suture anchor used for the surgery, pre-operative, and post-operative clinical scores such as Constant-Murley score, subjective shoulder value (SSV), and visual analog scale (VAS) were compared. The retear rates between groups were evaluated by ultrasound. RESULTS: Thirty-five IDR and thirty-five TOE-SB repairs were enrolled. The IDR technique required much fewer anchors than TOE-SB did to complete the cuff repair. The mean operation time in IDR and TOE-SB group were 86(18.23), and 114(18.7) (min), respectively (P <  0.01). The mean number of anchors used to complete the cuff repair was 2(0.17) in IDR and 3(0.61) in TOE-SB (P <  0.01). The Constant-Murley score improved from 34.9 ± 6.6 to 80.6 ± 9.4 in the IDR group, and 37.4 ± 6 to 81.9 ± 4.6 in the TOE-SB group (both P <  0.001). SSV improved from 24.6 ± 9.6 to 79.3 ± 10.6 in the IDR, and 27.9 ± 9 to 82.9 ± 6.9 in the TOE-SB group (both P <  0.001). VAS improved from 7.9 ± 0.6 to 1.5 ± 0.7 in the IDR, and 8 ± 0.5 to 1.3 ± 0.6 in the TOE-SB group (both P <  0.001) at final follow-up. No significant difference was found between the retear rates (14.3% in the IDR vs. 17.1% in the TOE-SB, respectively) in the 2-year follow-up. CONCLUSIONS: Both IDR and TOE-SB group provided comparable clinical results and retear rates for medium to massive posterosuperior rotator cuff tears. The surgical time and number of anchors used were less in the IDR group than in the TOE-SB group.

Robust Nanoparticle-Derived Lubricious Antibiofilm Coating for Difficult-to-Coat Medical Devices with Intricate Geometry.

A major medical device-associated complication is the biofilm-related infection post-implantation. One promising approach to prevent this is to coat already commercialized medical devices with effective antibiofilm materials. However, developing a robust high-performance antibiofilm coating on devices with a nonflat geometry remains unmet. Here, we report the development of a facile scalable nanoparticle-based antibiofilm silver composite coating with long-term activity applicable to virtually any objects including difficult-to-coat commercially available medical devices utilizing a catecholic organic-aqueous mixture. Using a screening approach, we have identified a combination of the organic-aqueous buffer mixture which alters polycatecholamine synthesis, nanoparticle formation, and stabilization, resulting in controlled deposition of in situ formed composite silver nanoparticles in the presence of an ultra-high-molecular-weight hydrophilic polymer on diverse objects irrespective of its geometry and chemistry. Methanol-mediated synthesis of polymer-silver composite nanoparticles resulted in a biocompatible lubricious coating with high mechanical durability, long-term silver release (∼90 days), complete inhibition of bacterial adhesion, and excellent killing activity against a diverse range of bacteria over the long term. Coated catheters retained their excellent activity even after exposure to harsh mechanical challenges (rubbing, twisting, and stretching) and storage conditions (>3 months stirring in water). We confirmed its excellent bacteria-killing efficacy (>99.999%) against difficult-to-kill bacteria (Proteus mirabilis) and high biocompatibility using percutaneous catheter infection mice and subcutaneous implant rat models, respectively, in vivo. The developed coating approach opens a new avenue to transform clinically used medical devices (e.g., urinary catheters) to highly infection-resistant devices to prevent and treat implant/device-associated infections.

No association of postoperative opioid usage with long-term surgery outcomes in patients with liver cancer: a population-based retrospective cohort study.

ABSTRACT: Hepatocellular carcinoma (HCC) is a fatal cancer worldwide, and surgical resection remains the standard treatment. Postoperative opioid prescription has been believed to affect cancer recurrence through complex biological pathways. We conducted a retrospective cohort study using the Longitudinal Health Insurance Database of Taiwan to evaluate the relationship between postoperative opioid use and long-term surgical outcomes of patients with HCC. This study had a retrospective cohort design. In total, 812 patients older than 20 years who underwent hepatectomy because of HCC were included. The exposure group comprised patients who used opioids during hospitalization postoperatively. The comparison group included those who never used opioids during hospitalization postoperatively. A Cox proportional hazards model was used to evaluate the overall survival or recurrence-free survival rate between the opioid group and the nonopioid group. A total of 530 patients received opioids postoperatively and 282 patients did not. The hazard ratios of overall survival and recurrence-free survival were 1.10 (95% confidence interval [CI], 0.85-1.41) and 1.15 (95% CI, 0.91-1.46), respectively. Total postoperative opioids were converted into oral morphine milligram equivalents and then divided into 3 equal subgroups: low dose, <40 mg; medium dose, 40 to 144 mg; and high dose, ≥145 mg. The hazard ratios of overall survival were 0.88 (95% CI, 0.63-1.24) for the low-dose group, 1.27 (95% CI, 0.92-1.74) for the medium-dose group, and 1.14 (95% CI, 0.83-1.58) for the high-dose group. Postoperative opioids do not affect overall and recurrence-free survival in patients undergoing hepatectomy or liver transplantation because of HCC. Cancer recurrence should not be a clinical concern regarding postoperative opioid prescription.

Genetic and Functional Effects of Adiponectin in Type 2 Diabetes Mellitus Development.

Diabetes mellitus (DM) is a common chronic metabolic disease, and the C57BLKsJ-db/db mice are good animal models for type 2 diabetes mellitus (T2DM). In this study, Western blotting and immunohistochemistry (IHC) were employed to examine the protein expression of adiponectin in the liver tissues of T2DM mice with different disease courses (4, 16, and 32 weeks). Adiponectin expression reduced in the liver tissues of T2DM mice in different disease courses. The genotypic and allelic frequencies of the adiponectin gene rs1063538 and rs2241766 single nucleotide polymorphisms (SNPs) in a Taiwanese population (570 T2DM patients and 1700 controls) were investigated. Based on the genetic distribution of the rs2241766 locus, the distribution frequency of the T allele in the T2DM group (72.8%) was higher than in the control group (68.8%). Individuals carrying the G allele had a 0.82-fold greater risk of developing T2DM than individuals carrying the T allele. Differences were evident in the genotypic and allelic distributions (p < 0.05). Enzyme-linked immunosorbent assay (ELISA) was used to measure changes in serum adiponectin protein concentrations in the healthy population and in patients with T2DM. Serum adiponectin concentration in patients with T2DM was lower than in the control group. In summary, adiponectin was determined to be a T2DM susceptibility gene and may be involved in T2DM progression.

CFTR Modulators: From Mechanism to Targeted Therapeutics.

People with cystic fibrosis (CF) suffer from a multi-organ disorder caused by loss-of-function variants in the gene encoding the epithelial anion channel cystic fibrosis transmembrane conductance regulator (CFTR). Tremendous progress has been made in both basic and clinical sciences over the past three decades since the identification of the CFTR gene. Over 90% of people with CF now have access to therapies targeting dysfunctional CFTR. This success was made possible by numerous studies in the field that incrementally paved the way for the development of small molecules known as CFTR modulators. The advent of CFTR modulators transformed this life-threatening illness into a treatable disease by directly binding to the CFTR protein and correcting defects induced by pathogenic variants. In this chapter, we trace the trajectory of structural and functional studies that brought CF therapies from bench to bedside, with an emphasis on mechanistic understanding of CFTR modulators.

Durable Surfaces from Film-Forming Silver Assemblies for Long-Term Zero Bacterial Adhesion without Toxicity.

The long-term prevention of biofilm formation on the surface of indwelling medical devices remains a challenge. Silver has been reutilized in recent years for combating biofilm formation due to its indisputable bactericidal potency; however, the toxicity, low stability, and short-term activity of the current silver coatings have limited their use. Here, we report the development of silver-based film-forming antibacterial engineered (SAFE) assemblies for the generation of durable lubricous antibiofilm surface long-term activity without silver toxicity that was applicable to diverse materials via a highly scalable dip/spray/solution-skinning process. The SAFE coating was obtained through a large-scale screening, resulting in effective incorporation of silver nanoparticles (∼10 nm) into a stable nonsticky coating with high surface hierarchy and coverage, which guaranteed sustained silver release. The lead coating showed zero bacterial adhesion over a 1 month experiment in the presence of a high load of diverse bacteria, including difficult-to-kill and stone-forming strains. The SAFE coating showed high biocompatibility and excellent antibiofilm activity in vivo.

Open the Technical Black Box of Tumor Mutational Burden (TMB): Factors Affecting Harmonization and Standardization of Panel-Based TMB.

As tumor mutational burden (TMB) has been approved as a predictive biomarker for immune checkpoint inhibitors (ICIs), next-generation sequencing (NGS) TMB panels are being increasingly used clinically. However, only a few of them have been validated in clinical trials or authorized by administration. The harmonization and standardization of TMB panels are thus essential for clinical implementation. In this review, preanalytic, sequencing, bioinformatics and interpretative factors are summarized to provide a comprehensive picture of how the different factors affect the estimation of panel-based TMB. Among the factors, poor DNA quality, improper formalin fixation and residual germline variants after filtration may overestimate TMB, while low tumor purity may decrease the sensitivity of the TMB panel. In addition, a small panel size leads to more variability when comparing with true TMB values detected by whole-exome sequencing (WES). A panel covering a genomic region of more than 1Mb is more stable for harmonization and standardization. Because the TMB estimate reflects the sum of effects from multiple factors, deliberation based on laboratory and specimen quality, as well as clinical information, is essential for decision making.

Percutaneous delivery of self-propelling thrombin-containing powder increases survival from noncompressible truncal hemorrhage in a swine model of coagulopathy and hypothermia.

BACKGROUND: Noncompressible truncal hemorrhage (NCTH) remains a leading cause of preventable death on the battlefield. Definitively managing severe NCTH requires surgery within the first hour after injury, which is difficult when evacuating casualties from remote and austere environments. During delays to surgery, hemostatic interventions that are performed prehospital can prevent coagulopathy and hemorrhagic shock and increase the likelihood that casualties survive to receive definitive care. We previously reported that a self-propelling thrombin-containing powder (SPTP) can be delivered percutaneously into the abdomen as a minimally invasive intervention and can self-disperse through pooled blood to deliver the hemostatic agents thrombin and tranexamic acid locally to noncompressible intracavitary wounds. We hypothesized that, in swine with massive NCTH, dilutional coagulopathy, and hypothermia, delivering SPTP could extend survival times. METHODS: Ten swine (n = 5 per group) underwent NCTH from a Grade V liver injury following a midline laparotomy. The laparotomy was closed with sutures afterwards, creating a hemoperitoneum, and animals were managed with crystalloid fluid resuscitation, or crystalloid resuscitation and SPTP. Self-propelling thrombin-containing powder was delivered into the closed abdomen using a CO 2 -powered spray device and a catheter placed into the hemoperitoneum, entering through the upper right quadrant using the Seldinger technique. Survival to 1 and 3 hours was recorded. In an additional animal, hemorrhage was created laparoscopically, and SPTP was imaged in situ within the abdomen to visually track dispersion of the particles. RESULTS: Self-propelling thrombin-containing powder dispersed as far as 35 ± 5.0 cm within the abdomen. It increased survival to 1 and 3 hours (Kaplan-Meier p = 0.007 for both). The median survival time was 61 minutes with SPTP and 31 minutes without ( p = 0.016). CONCLUSION: Self-propelling thrombin-containing powder effectively disperses medications throughout a hemoperitoneum and increases survival in a model of NCTH. It is a promising strategy for nonsurgical management of NCTH, warranting further testing of its safety and efficacy.

Increasing arsenic accumulation as an implication of climate change: a case study using red algae.

Climate change due to an increasing concentration of carbon dioxide in the atmosphere is a global issue. It can impact aquatic environments by affecting water flow, pollutant transformation and migration, and other toxicant-related effects. We assessed the interactive effects of temperature warming and pH changes on variations in accumulation of total arsenic (AsT) in the red alga Sarcodia suae at different levels of arsenite (AsIII). Result showed that AsT variations in the alga were moderated by significant joint effects of warming temperature and/or increasing pH levels and their interactions with increasing AsIII concentrations. Our study suggests possible deleterious impacts on macroalgal populations due to toxicological effects associated with prevailing environmental conditions. Therefore, improved pollution management, climate change adaptation, and mitigation strategies are needed to deal with current environmental issues and As aggravation.

Association Between Aortic Aneurysm and Aortic Dissection With Fluoroquinolones Use in Patients With Urinary Tract Infections: A Population-Based Cohort Study.

Background Fluoroquinolones are first-line antibiotics recommended for the treatment of complicated urinary tract infections (UTIs), with frequent reports of adverse effects of aortic aneurysm (AA) and aortic dissection (AD). We examined whether fluoroquinolones can increase the risk of AA and AD in patients with UTIs in the Taiwanese population. Methods and Results We used the National Health Insurance Research Database to identify patients diagnosed with UTIs under single antibiotic treatment of fluoroquinolones and first-, second-, or third-generation cephalosporins. An AA and AD diagnosis within a year constituted the study event. Multivariable analysis with a multiple Cox regression model was applied for comparing the hazard risk of AA and AD between fluoroquinolones and first- or second-generation cephalosporins. Propensity score matching was performed to reduce the potential for bias caused by measured confounding variables. Among 1 249 944 selected patients with UTIs, 28 568 patients were assigned to each antibiotic group after propensity score matching. The incidence of AA and AD was not significantly different between the fluoroquinolones and first- or second-generation cephalosporins (adjusted HR [aHR], 0.86 [95% CI, 0.59-1.27]). However, the mortality increased in the fluoroquinolones group (aHR, 1.10 [95% CI, 1.04-1.16]). Conclusions Compared with first- or second-generation cephalosporins, fluoroquinolones were not associated with increased risk of AA and AD in patients with UTI. However, a significant risk of mortality was still found in patients treated with fluoroquinolones. The priority is to control infections with adequate antibiotics rather than exclude fluoroquinolones considering the risk of AA and AD for patients with UTI.

Enhanced Colaconema formosanum biomass and phycoerythrin yield after manipulating inorganic carbon, irradiance, and photoperiod.

Due to an increasing CO2 concentration leading to global warming, the techniques as carbon capture utilization and storage are currently critical issues. This study aimed to investigate a cultivation strategy using optimal inorganic carbon level, irradiance, and photoperiod for producing the highest biomass and photosynthesis pigment contents (chlorophyll and phycobiliprotein) in the macroalga Colaconema formosanum. The results revealed that adding 1 g L-1 carbon increases phycoerythrin ratio by 12.52-13.74% and decreases allophycocyanin by 10.4-9.57%. Optimal conditions can increase algal growth by 60%, providing 5-6 mg g-1 total phycobiliprotein and 650-680 µg g-1 total chlorophyll. The results in this study illustrate the sensitivity of photosynthesis pigment after treatment with carbon, and suggest a hypothesis explaining the mechanism. The results also provide a feasible use of carbon for high-value large-scale production of pigment in the macroalgae industry.

Rheological and clot microstructure evaluation of heparin neutralization by UHRA and protamine.

The current study reports the use of small amplitude oscillatory rheometry to investigate the dynamics of blood clot formation upon heparin neutralization under three different oscillatory frequencies, two of which were mimicking physiological heart rates. We utilized two different heparin antidotes, namely protamine and newly developed universal heparin reversal agent (UHRA-7), at different concentrations to determine the quality of blood clot formed upon heparin neutralization by analyzing several key rheological parameters. Scanning electron microscopy (SEM) was used to determine the morphology and microstructure of the blood clot after heparin neutralization to support the rheological observations. The current study revealed that the structure of blood clots formed had significant differences when an oscillatory frequency that mimicked the physiological heart rate was used in comparison to a lower frequency commonly used in current clinical measurements. The limited working dose range for protamine and its intrinsic anticoagulation behaviour was observed. The neutralization profile of UHRA-7 showed a large window of activity. The global assessment of rheological parameters and microstructure of the clot together revealed additional details describing anticoagulant reversal and blood coagulation dynamics by relating the blood clot's fiber thickness and the oscillatory measurements, including storage modulus and blood clot's contractile force. Additionally, a mechanical characterization was conducted to provide a further assessment of blood coagulation using the rheological data.

Extraction Procedure, Characteristics, and Feasibility of Caulerpa microphysa (Chlorophyta) Polysaccharide Extract as a Cosmetic Ingredient.

The green alga Caulerpa microphysa, which is native to Taiwan, has a relatively high economic value and a well-developed culture technique, and is used mainly as a foodstuff. Its extract has been shown to exhibit antitumor properties, but the polysaccharide content of the extract and its anti-inflammatory and wound-healing effects and moisture-absorption and -retention capacity remain unknown. Hence, the objective of this study was to evaluate the potential of the polysaccharides in C. microphysa extract (CME) for use in cosmetics. The overall polysaccharide yield from the CME was 73.93% w/w, with four molecular weight fractions. The polysaccharides comprised 59.36 mol% mannose, 27.16 mol% glucose, and 13.48 mol% galactose. In addition, the CME exhibited strong antiallergic, wound-healing, transdermal-delivery, and moisture-absorption and -retention effects. In conclusion, the results suggested that CME potentially has anti-inflammatory and wound-healing effects and a good moisture capacity, which can be used in cosmetic applications.

Deep Venous Thrombosis and Risk of Consequent Sepsis Event: A Retrospective Nationwide Population-Based Cohort Study.

Deep vein thrombosis causes several acute and chronic vessel complications and puts patients at risk of subsequent sepsis development. This unique study aimed to estimate the risk of sepsis development in DVT patients compared with non-DVT patients. This population-based cohort study used records of a longitudinal health insurance database containing two million patients defined in Taiwan's National Health Insurance Research Database (NHIRD). Our study included patients aged over 20 years with a new diagnosis of DVT with at least two outpatient department visits or an admission between 2001 and 2014. Patients with a diagnosis of sepsis before the index date were excluded. Propensity score matching (PSM) was used to homogenize the baseline characteristics between the two groups. To define the independent risk of the DVT group, a multivariate Cox proportional hazard model was used to estimate the hazard ratios. After PSM, the DVT group (n = 5753) exhibited a higher risk of sepsis (adjusted hazard ratio, aHR, 1.74; 95% CI, 1.59-1.90) compared with non-DVT group (n = 5753). Patients with an increased risk of sepsis were associated with being elderly aged, male, having diabetes, chronic kidney disease, chronic obstructive pulmonary disease, stroke, malignancy, and use of antibiotics. In conclusion, this population-based cohort study demonstrated an increased risk of sepsis in DVT patients compared with non-DVT patients. Thus, early prevention and adequate treatment of DVT is necessary in clinical practice.

Functional stability of CFTR depends on tight binding of ATP at its degenerate ATP-binding site.

Opening of the cystic fibrosis transmembrane conductance regulator (CFTR) channel is coupled to the motion of its two nucleotide-binding domains: they form a heterodimer sandwiching two functionally distinct ATP-binding sites (sites 1 and 2). While active ATP hydrolysis in site 2 triggers rapid channel closure, the functional role of stable ATP binding in the catalysis-incompetent (or degenerate) site 1, a feature conserved in many other ATP-binding cassette (ABC) transporter proteins, remains elusive. Here, we found that CFTR loses its prompt responsiveness to ATP after the channel is devoid of ATP for tens to hundreds of seconds. Mutants with weakened ATP binding in site 1 and the most prevalent disease-causing mutation, F508del, are more vulnerable to ATP depletion. In contrast, strengthening ligand binding in site 1 with N6 -(2-phenylethyl)-ATP, a high-affinity ATP analogue, or abolishing ATP hydrolysis in site 2 by the mutation D1370N, helps sustain a durable function of the otherwise unstable mutant channels. Thus, tight binding of ATP in the degenerate ATP-binding site is crucial to the functional stability of CFTR. Small molecules targeting site 1 may bear therapeutic potential to overcome the membrane instability of F508del-CFTR. KEY POINTS: During evolution, many ATP-binding cassette transporters - including the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, whose dysfunction causes cystic fibrosis (CF) - lose the ability to hydrolyse ATP in one of the two ATP-binding sites. Here we show that tight ATP binding at this degenerate site in CFTR is central for maintaining the stable, robust function of normal CFTR. We also demonstrate that membrane instability of the most common CF-causing mutant, F508del-CFTR, can be rescued by strengthening ATP binding at CFTR's degenerate site. Our data thus explain an evolutionary puzzle and offer a potential therapeutic strategy for CF.