3D-printed titanium scaffolds loaded with gelatin hydrogel containing strontium-doped silver nanoparticles promote osteoblast differentiation and antibacterial activity for bone tissue engineering.

Bone tissue engineering offers a promising alternative to stimulate the regeneration of damaged tissue, overcoming the limitations of conventional autografts and allografts. Recently, titanium alloy (Ti) implants have garnered significant attention for treating critical-sized bone defects, especially with the advancement of 3D printing technology. Although Ti alloys have impressive versatility, their lack of cellular adhesion, osteogenic and antibacterial properties are significant factors that contribute to their failure. Hence, to overcome these obstacles, this study aimed to incorporate osteoinductive and antibacterial cue-loaded hydrogels into 3D-printed Ti (3D-Ti) scaffolds. 3D-Ti scaffolds were synthesized using the direct metal laser sintering method and loaded with a gelatin (Gel) hydrogel containing strontium-doped silver nanoparticles (Sr-Ag NPs). Compared with Ag NPs, Sr-doped Ag NPs increased the expression of Runx2 mRNA, which is a key bone transcription factor. We subjected the bioactive 3D-hybrid scaffolds (3D-Ti/Gel/Sr-Ag NPs) to physicochemical and material characterization, followed by cytocompatibility and osteogenic evaluation. The microporous and macroporous topographies of the scaffolds with Sr-Ag NPs showed increased Runx2 expression and matrix mineralization, with potent antibacterial properties. Therefore, the 3D-Ti scaffolds incorporated with Sr-Ag NP-loaded Gel hydrogels favored osteoblast differentiation and antibacterial activity, indicating their potential for orthopedic applications.

Genomic, epigenomic and transcriptomic landscape of glioblastoma.

The mostly aggressive and extremely malignant type of central nervous system is Glioblastoma (GBM), which is characterized by an extremely short average survival time of lesser than 16 months. The primary cause of this phenomenon can be attributed to the extensively altered genome of GBM, which is characterized by the dysregulation of numerous critical signaling pathways and epigenetics regulations associated with proliferation, cellular growth, survival, and apoptosis. In light of this, different genetic alterations in critical signaling pathways and various epigenetics regulation mechanisms are associated with GBM and identified as distinguishing markers. Such GBM prognostic alterations are identified in PI3K/AKT, p53, RTK, RAS, RB, STAT3 and ZIP4 signaling pathways, metabolic pathway (IDH1/2), as well as alterations in epigenetic regulation genes (MGMT, CDKN2A-p16INK4aCDKN2B-p15INK4b). The exploration of innovative diagnostic and therapeutic approaches that specifically target these pathways is utmost importance to enhance the future medication for GBM. This study provides a comprehensive overview of dysregulated epigenetic mechanisms and signaling pathways due to mutations, methylation, and copy number alterations of in critical genes in GBM with prevalence and emphasizing their significance.

Rapid nucleation and optimal surface-ligand interaction stabilize wurtzite MnSe.

Non-native structures (NNS) differ in discrete translational symmetry from the bulk ground state native structure (NS). To explore the extent of deconvolution of various factors relevant to the stabilization of the wurtzite/NNS of MnSe via a heat-up method, we performed experiments using various ligands (oleic acid, oleylamine, octadecylamine, stearic acid, and octadecene), solvents (tetraethylene glycol and octadecene), and precursor salts (manganese chloride and manganese acetate). Experiments suggest that oleic acid in the presence of tetraethylene glycol and oleylamine in the presence of octadecene stabilize wurtzite/NNS. Further, density functional theory (DFT) computations explore the interaction between the functional groups in ligands and the most exposed surfaces of wurtzite/NNS and rocksalt/NS polymorphs. Computations suggest that the interactions between relevant surface facets with carboxylic acid and the double bond functional groups suppress the phase transformation from NNS to NS. In addition, the ionizability of the precursor salt also determines the rate of formation of the metal-ligand complex and the rate of nucleation. Consequently, the formation rate of the Mn-ligand complex is expected to be greater in the case of chloride salt than acetate salt because the chloride salt has higher ionizability in ethylene glycol. From the above, we conclude that the kinetics of the wurtzite/NNS to rocksalt/NS phase transformation depends mainly on two factors: (1) nucleation/growth kinetics which is controlled by the ionizability of the precursor salt, solvent, and stability of the metal-ligand complex, and (2) the activation energy barrier of the NNS to NS conversion which is controlled by surface energy minimization with the ligand.

Face-specific identification impairments following sight-providing treatment may be alleviated by an initial period of low visual acuity.

Identifying faces requires configural processing of visual information. We previously proposed that the poor visual acuity experienced by newborns in their first year of life lays the groundwork for such configural processing by forcing integration over larger spatial fields. This hypothesis predicts that children treated for congenital cataracts late in life will exhibit persistent impairments in face- but not object-identification, because they begin their visual journey with higher than newborn acuity. This would not be the case for patients whose pretreatment condition has allowed for initial low acuity vision, like that of a newborn. Here, we test this prediction by assessing the development of facial identification skill in three groups: patients treated for congenital cataracts whose pretreatment visual acuity was worse than that of a newborn, patients whose pretreatment acuity was better than that of a newborn, and age-matched controls. We find that while both patient groups show significant gains in object-identification, the emergence of face identification is determined by pretreatment acuity: patients with pre-operative acuity worse than a newborn did not show any improvements on face-identification tasks despite years of visual experience, whereas those with pretreatment acuity comparable to a newborn improved on both the object- and face-identification tasks. These findings not only answer our research question but also provide new insights into the role of early visual acuity in facial identification development. We discuss these results in the context of both typical and atypical visual development.

Degradation of organic Pollutant by Using of BiVO4-NiFe2O4 Heterostructure Photocatalyst under Visible Light Irradiation: Assessment of Detoxicity Study Using Cirrhinus mrigala.

The current study mainly concentrates on the photocatalytic activity of composite nanomaterial of BiVO4 (BVO), NiFe2O4 (NFO), and BiVO4-NiFe2O4 (BVO-NFO) under visible light. Among these, BVO-NFO composite degrades crystal violet dye within 60 min with a percentage degradation of 95.65% under visible light illumination. The BVO-NFO composite exhibits better photodegradation performance, which can be attributed to the effective light absorption and reduced recombination of the photoexcited charge carriers. Additionally, by applying a magnetic field, the BVO-NFO composite can be magnetically recovered by using the magnet for subsequent recycling. The synthesized composite was characterized using optical techniques like X-ray diffraction, ultraviolet diffuse reflectance spectroscopy, scanning electron microscopy, Brunauer-Emmett-Teller, and energy dispersive X-ray analysis. The effect of dye, before and after degradation, on vital organs of fish species was examined such as fish gill (pulmonary-toxicity), fish liver (hepato-toxicity), fish kidney (renal toxicity), fish brain (neural toxicity), and fish muscle (myopathy). This work offers a clear and practical method for designing a highly crystalline semiconductor photocatalyst for dye degradation and the remediation of industrial wastewater.

Post-tubercular Lumbosacral Kyphotic Deformity in a 11-Year-Old Child: A Case Report.

CASE: An 11-year-old girl with intact neurology presented with a lumbosacral kyphotic deformity due to healed tuberculosis. Radiological imaging showed sagittal balanced spine with compensatory thoracic lordosis and cervical kyphosis. She underwent L4 and L5 posterior vertebral column resection (PVCR) with posterior instrumentation from L2 to pelvis. The patient demonstrated immediate correction of compensatory curves postoperatively. At 3-year follow-up, she returned to her activities of daily living with Oswestry Disability Index and Scoliosis Research Society scores of 12 and 4.8% respectively. CONCLUSION: Pediatric post-tubercular deformities in the lumbosacral region are rare. They can cause secondary changes in other regions, such as the loss of thoracic kyphosis or cervical lordosis. These deformities should be addressed at an early age to prevent structural changes in compensatory curves.

Identification and characterization of multidomain monothiol glutaredoxin 3 from diploblastic Hydra.

Intracellular antioxidant glutaredoxin controls cell proliferation and survival. Based on the active site, structure, and conserved domain motifs, it is classified into two classes. Class I contains dithiol Grxs with two cysteines in the consensus active site sequence CXXC, while class II has monothiol Grxs with one cysteine residue in the active site. Monothiol Grxs can also have an additional N-terminal thioredoxin (Trx)-like domain. Previously, we reported the characterization of Grx1 from Hydra vulgaris (HvGrx1), which is a dithiol isoform. Here, we report the molecular cloning, expression, analysis, and characterization of another isoform of Grx, which is the multidomain monothiol glutaredoxin-3 from Hydra vulgaris (HvGrx3). It encodes a protein with 303 amino acids and is significantly larger and more divergent than HvGrx1. In-silico analysis revealed that Grx1 and Grx3 have 22.5% and 9.9% identical nucleotide and amino acid sequences, respectively. HvGrx3 has two glutaredoxin domains and a thioredoxin-like domain at its amino terminus, unlike HvGrx1, which has a single glutaredoxin domain. Like other monothiol glutaredoxins, HvGrx3 failed to reduce glutathione-hydroxyethyl disulfide. In the whole Hydra, HvGrx3 was found to be expressed all over the body column, and treatment with H2O2 led to a significant upregulation of HvGrx3. When transfected in HCT116 (human colon cancer cells) cells, HvGrx3 enhanced cell proliferation and migration, indicating that this isoform could be involved in these cellular functions. These transfected cells also tolerate oxidative stress better.

Integrative multi-region molecular profiling of primary prostate cancer in men with synchronous lymph node metastasis.

Localized prostate cancer is frequently composed of multiple spatially distinct tumors with significant inter- and intra-tumoral molecular heterogeneity. This genomic diversity gives rise to many competing clones that may drive the biological trajectory of the disease. Previous large-scale sequencing efforts have focused on the evolutionary process in metastatic prostate cancer, revealing a potential clonal progression to castration resistance. However, the clonal origin of synchronous lymph node (LN) metastases in primary disease is still unknown. Here, we perform multi-region, targeted next generation sequencing and construct phylogenetic trees in men with prostate cancer with synchronous LN metastasis to better define the pathologic and molecular features of primary disease most likely to spread to the LNs. Collectively, we demonstrate that a combination of histopathologic and molecular factors, including tumor grade, presence of extra-prostatic extension, cellular morphology, and oncogenic genomic alterations are associated with synchronous LN metastasis.

Development and Validation of an 18-Gene Urine Test for High-Grade Prostate Cancer.

Importance: Benefits of prostate cancer (PCa) screening with prostate-specific antigen (PSA) alone are largely offset by excess negative biopsies and overdetection of indolent cancers resulting from the poor specificity of PSA for high-grade PCa (ie, grade group [GG] 2 or greater). Objective: To develop a multiplex urinary panel for high-grade PCa and validate its external performance relative to current guideline-endorsed biomarkers. Design, Setting, and Participants: RNA sequencing analysis of 58 724 genes identified 54 markers of PCa, including 17 markers uniquely overexpressed by high-grade cancers. Gene expression and clinical factors were modeled in a new urinary test for high-grade PCa (MyProstateScore 2.0 [MPS2]). Optimal models were developed in parallel without prostate volume (MPS2) and with prostate volume (MPS2+). The locked models underwent blinded external validation in a prospective National Cancer Institute trial cohort. Data were collected from January 2008 to December 2020, and data were analyzed from November 2022 to November 2023. Exposure: Protocolized blood and urine collection and transrectal ultrasound-guided systematic prostate biopsy. Main Outcomes and Measures: Multiple biomarker tests were assessed in the validation cohort, including serum PSA alone, the Prostate Cancer Prevention Trial risk calculator, and the Prostate Health Index (PHI) as well as derived multiplex 2-gene and 3-gene models, the original 2-gene MPS test, and the 18-gene MPS2 models. Under a testing approach with 95% sensitivity for PCa of GG 2 or greater, measures of diagnostic accuracy and clinical consequences of testing were calculated. Cancers of GG 3 or greater were assessed secondarily. Results: Of 761 men included in the development cohort, the median (IQR) age was 63 (58-68) years, and the median (IQR) PSA level was 5.6 (4.6-7.2) ng/mL; of 743 men included in the validation cohort, the median (IQR) age was 62 (57-68) years, and the median (IQR) PSA level was 5.6 (4.1-8.0) ng/mL. In the validation cohort, 151 (20.3%) had high-grade PCa on biopsy. Area under the receiver operating characteristic curve values were 0.60 using PSA alone, 0.66 using the risk calculator, 0.77 using PHI, 0.76 using the derived multiplex 2-gene model, 0.72 using the derived multiplex 3-gene model, and 0.74 using the original MPS model compared with 0.81 using the MPS2 model and 0.82 using the MPS2+ model. At 95% sensitivity, the MPS2 model would have reduced unnecessary biopsies performed in the initial biopsy population (range for other tests, 15% to 30%; range for MPS2, 35% to 42%) and repeat biopsy population (range for other tests, 9% to 21%; range for MPS2, 46% to 51%). Across pertinent subgroups, the MPS2 models had negative predictive values of 95% to 99% for cancers of GG 2 or greater and of 99% for cancers of GG 3 or greater. Conclusions and Relevance: In this study, a new 18-gene PCa test had higher diagnostic accuracy for high-grade PCa relative to existing biomarker tests. Clinically, use of this test would have meaningfully reduced unnecessary biopsies performed while maintaining highly sensitive detection of high-grade cancers. These data support use of this new PCa biomarker test in patients with elevated PSA levels to reduce the potential harms of PCa screening while preserving its long-term benefits.

Development of a Cissus quadrangularis-Doped Extracellular Matrix and a Hyaluronic Acid-Incorporated Scaffold for Periodontal Regeneration: An In Vitro Study.

PURPOSE: The study aimed to analyze whether adding Cissus quadrangularis (CQ) extract and the extracellular matrix of ovine tendon (TENDON) increases the regenerative potential of mesenchymal stem cells produced in hyaluronic acid (HA) scaffolds for tenogenesis. MATERIALS AND METHODS: Fifty grams of powdered CQ was mixed with 250 mL of ethanol to prepare the extract. Two grams of hyaluronic acid powder was added to 100 mL of distilled water to make the HA solution. The ovine tendon was decellularized using a mixture of 10% phosphate-buffered saline (PBS), sodium dodecyl sulfate (SDS), and Triton-X. The hydrogel samples were prepared by mixing the extracellular matrix of tendon, HA, and CQ, after which they were divided into study groups such as HA, HA + CQ, HA + TENDON, and HA + CQ + TENDON. Scanning electron microscopy (SEM) analysis, swelling analysis, differentiation analysis, compression test, compatibility assay, and tenogenesis assay were later conducted. RESULTS: The morphology of the samples was analyzed using SEM. Low levels of swelling of the hydrogels were observed. Cells were found to be viable and showed good differentiation and tenogenesis. Optimal compression levels were observed, and the properties of the prepared hydrogels were satisfactory. CONCLUSION: The results suggest that the addition of CQ considerably increases the tenogenic potential of the extracellular matrix/HA scaffold. Hence, it can be used as a regenerative material for periodontal tissue regeneration.

Hyaluronic Acid Hydrogel Combined With Ocimum sanctum and Tendon-Derived Extracellular Matrix Enhances Tenogenesis in Periodontal Ligament Stem Cells.

Background Ocimum sanctum (OS) is a medicinal plant with antioxidant, anti-cancer, anti-diabetic, antimicrobial, and anti-inflammatory activities. Extracellular matrix (ECM) maintains the structural stability of tissues. Hyaluronic acid (HA), which is used in hydrogel fabrication and osteochondral regeneration, increases cell viability and the expression of marker genes. Periodontal ligament stem cells (PDLSC), which are a type of mesenchymal stem cells (MSC), have self-renewing capacity and they prevent teratoma formation and promote tendon (TEN) regeneration. The aim of this study is to incorporate the phytochemical effects of Ocimum sanctum into hyaluronic acid hydrogel scaffolds made with the MSCs in tendon ECM for increased tissue regeneration. Materials & methods Ocimum sanctum extract and methacrylated hyaluronic acid (HA-MA) were prepared. An ovine tendon sample was decellularised to obtain the ECM. The study groups of HA, TEN, HA_OS, HA_TEN, and HA_OS_TEN were prepared. The presence of tendon cells was confirmed by picrosirius red staining and the hydrogel scaffolds were analysed using scanning electron microscopy (SEM), swelling, differentiation, compression, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) compatibility analyses. Results The morphology of the samples was analysed by SEM analysis. The HA_OS_TEN sample showed the highest rate of tenogenesis, lowest swelling, high cell viability and differentiation, and optimal compression rates. Conclusion This study showed that hyaluronic acid combined with Ocimum sanctum and tendon ECM is a very good conjugation for the preparation of hydrogel scaffolds for tendon tissue regeneration using MSCs.

Dynamics, allostery, and stabilities of whole virus particles by amide hydrogen/deuterium exchange mass spectrometry (HDXMS).

X-ray crystallography and cryo-electron microscopy have enabled the determination of structures of numerous viruses at high resolution and have greatly advanced the field of structural virology. These structures represent only a subset of snapshot end-state conformations, without describing all conformational transitions that virus particles undergo. Allostery plays a critical role in relaying the effects of varied perturbations both on the surface through environmental changes and protein (receptor/antibody) interactions into the genomic core of the virus. Correspondingly, allostery carries implications for communicating changes in genome packaging to the overall stability of the virus particle. Amide hydrogen/deuterium exchange mass spectrometry (HDXMS) of whole viruses is a powerful probe for uncovering virus allostery. Here we critically discuss advancements in understanding virus dynamics by HDXMS with single particle cryo-EM and computational approaches.

Analysis of the Tumor Immune Microenvironment (TIME) in Clear Cell Renal Cell Carcinoma (ccRCC) Reveals an M0 Macrophage-Enriched Subtype: An Exploration of Prognostic and Biological Characteristics of This Immune Phenotype.

There is a need to optimize the treatment of clear cell renal cell carcinoma (ccRCC) patients at high recurrence risk after nephrectomy. We sought to elucidate the tumor immune microenvironment (TIME) of localized ccRCC and understand the prognostic and predictive characteristics of certain features. The discovery cohort was clinically localized patients in the TCGA-Kidney Renal Clear Cell Carcinoma (KIRC) project (n = 382). We identified an M0 macrophage-enriched cluster (n = 25) in the TCGA-KIRC cohort. This cluster's median progression-free survival (PFS) and overall survival (OS) were 40.4 and 45.3 months, respectively, but this was not reached in the others (p = 0.0003 and <0.0001, respectively). Gene set enrichment (GSEA) analysis revealed an enrichment of epithelial to mesenchymal transition and cell cycle progression genes within this cluster, and these patients also had a lower predicted response to immune checkpoint blockade (ICB) (4% vs. 20-34%). An M0-enriched cluster (n = 9) with shorter PFS (p = 0.0006) was also identified in the Clinical Proteomics Tumor Analysis Consortium (CPTAC) cohort (n = 94). Through this characterization of the TIME in ccRCC, a cluster of patients defined by enrichment in M0 macrophages was identified that demonstrated poor prognosis and lower predicted ICB response. Pending further validation, this signature can identify localized ccRCC patients at high risk of recurrence after nephrectomy and who may require therapeutic approaches beyond ICB monotherapy.

Role of adenosine deaminase in prostate cancer progression.

Prostate cancer (PCa) is the second most common cancer and constitutes about 14.7% of total cancer cases. PCa is highly prevalent and more aggressive in African-American (AA) men than in European-American (EA) men. PCa tends to be highly heterogeneous, and its complex biology is not fully understood. We use metabolomics to better understand the mechanisms behind PCa progression and disparities in its clinical outcome. Adenosine deaminase (ADA) is a key enzyme in the purine metabolic pathway; it was found to be upregulated in PCa and is associated with higher-grade PCa and poor disease-free survival. The inosine-to-adenosine ratio, which is a surrogate for ADA activity was high in PCa patient urine and higher in AA PCa compared to EA PCa. To understand the significance of high ADA in PCa, we established ADA overexpression models and performed various in vitro and in vivo studies. Our studies have revealed that an acute increase in ADA expression during later stages of tumor development enhances in vivo growth in multiple pre-clinical models. Further analysis revealed that mTOR signaling activation could be associated with this tumor growth. Chronic ADA overexpression shows alterations in the cells' adhesion machinery and a decrease in cells' ability to adhere to the extracellular matrix in vitro. Losing cell-matrix interaction is critical for metastatic dissemination which suggests that ADA could potentially be involved in promoting metastasis. This is supported by the association of higher ADA expression with higher-grade tumors and poor patient survival. Overall, our findings suggest that increased ADA expression may promote PCa progression, specifically tumor growth and metastatic dissemination.

Knowledge and Attitude toward Antibiotic Use and Identification of Financially Feasible Options to Curb the Spread of Antibiotics in Environment.

A survey on antibiotic literacy in terms of the use and abuse of antibiotics to track and understand antibiotic consumption is crucial to optimize the use of antibiotics and minimizing antimicrobial resistance (AMR). Purposive random sampling, using the snow-ball questionnaire technique, was adopted to ensure that the respondents distributed across India, coming from rural and urban settings, were adolescents as well as adults and had completed at least the higher secondary school level of education. Respondents were divided into five subcategories. The questionnaire was distributed between April 2021 and July 2021, during the second COVID-19 wave in India. The survey questionnaire included 34 questions, comprising multiple-choice and 5-point Likert scale-type questions. This study composed of 972 respondents. Most respondents considered antibiotics safe and frequently failed to discriminate between the symptoms of bacterial and viral infections, most often leading to self-prescription. About 34% of the rural participants and 50% of the urban participants considered antibiotic resistance a serious health concern. Antibiotic prescriptions by the medical or paramedical practitioner were largely empirical. At least 95% of participants acknowledged having heard about antibiotics; nearly 20% of antibiotic consumption came from nonprescription users, while 30% had not completed their antibiotic therapy for a variety of reasons. Sixty-two percent consumed antibiotics to treat cold and flu symptoms. Results from the survey suggest the presence of a crucial gap between the respondents' perception of antibiotics and levels of information regarding antibiotic use and misuse. The present study may serve as a benchmark that strongly recommends a financially feasible policy, which includes educating society regarding the spread of AMR and its severe consequences by incorporating AMR into the curriculum at the levels of senior secondary school and higher education.

Regioselective ortho halogenation of N-aryl amides and ureas via oxidative halodeboronation: harnessing boron reactivity for efficient C-halogen bond installation.

The installation of the C-halogen bond at the ortho position of N-aryl amides and ureas represents a tool to prepare motifs that are ubiquitous in biologically active compounds. To construct such prevalent bonds, most methods require the use of precious metals and a multistep process. Here we report a novel protocol for the long-standing challenge of regioselective ortho halogenation of N-aryl amides and ureas using an oxidative halodeboronation. By harnessing the reactivity of boron over nitrogen, we merge carbonyl-directed borylation with consecutive halodeboronation, enabling the precise introduction of the C-X bond at the desired ortho position of N-aryl amides and ureas. This method offers an efficient, practical, and scalable solution for synthesizing halogenated N-heteroarenes under mild conditions, highlighting the superiority of boron reactivity in directing the regioselectivity of the reaction.

Nail-Patella Syndrome: A Case Series From Northern India.

The nail-patella syndrome (NPS) is an uncommon entity with a characteristic set of anomalies. The presence of classical tetrad of hypoplastic or absent fingernails, hypoplastic or absent patellae, bilateral iliac horns and varying grades of elbow deformities are well elucidated in the literature. The spectrum of clinical manifestation varies, resulting in very few cases presenting to the healthcare facility or being diagnosed appropriately. We, hereby, describe our experience of three separate cases of the NPS, diagnosed on clinical and radiological basis. All cases were diagnosed incidentally and none presented to us for consultation regarding the anomalies due to this disorder. In one of the cases, a young girl was managed medically for an associated abdominal complaint. Her father was also found with the clinical features of the disorder thus making the father-daughter duo, part of our series. One case presenting with a femur fracture was managed with fracture fixation surgery leading to an uneventful healing of fracture. There was neither a history of any other family member having similar anomalies nor other systemic disorders in all three cases. Knowledge of the condition may help in improving the diagnosis of NPS and enrich the medical literature.

Impaired cAMP processivity by phosphodiesterase-protein kinase A complexes in acrodysostosis.

Acrodysostosis represents a group of rare genetic disorders characterized by defective skeletal development and is often accompanied by intellectual disabilities. Mutations in the 3'5'cyclic AMP (cAMP)-dependent protein kinase (PKA) type I regulatory subunit isoform α (RIα) and phosphodiesterase (PDE) PDE4D have both been implicated in impaired PKA regulation in acrodysostosis. How mutations on PDEs and RIα interfere with the regulation of cAMP-PKA signaling is not understood. cAMP-PKA signaling can be described in two phases. In the activation phase, cAMP binding to RIα dissociates the free C-subunit (Catalytic subunit). PDEs hydrolyze cAMP bound to RIα, priming the cAMP-free RIα for reassociation with the C-subunit, thereby completing one PKA activation cycle. Signal termination is thus critical for resetting PKA to its basal state and promoting adaptation to hormonal hyperstimulation. This proceeds through formation of a transient signal termination RIα: PDE complex that facilitates cAMP channeling from the cAMP-binding domain of RIα to the catalytic site of PDE. Signal termination of cAMP-PKA proceeds in three steps: Step 1) Channeling: translocation of cAMP from the CNB of RIα to the PDE catalytic site for hydrolysis. Step 2) Processivity: binding of free cAMP from the cytosol at both CNBs of RIα. Step 3) Product (5'AMP) release from the PDE hydrolysis site through competitive displacement by a new molecule of cAMP that triggers subsequent activation cycles of PKA. We have identified the molecular basis for two acrodysostosis mutants, PDE (PDE8 T690P) and RIα (T207A), that both allosterically impair cAMP-PKA signal termination. A combination of amide hydrogen/deuterium exchange mass spectrometry (HDXMS) and fluorescence polarization (FP) reveals that PDE8 T690P and RIα T207A both blocked processive hydrolysis of cAMP by interfering with competitive displacement of product 5'AMP release from the nucleotide channel at the end of each round of cAMP hydrolysis. While T690P blocked product 5'AMP release from the PDE, T207A greatly slowed the release of the substrate from RIα. These results highlight the role of processivity in cAMP hydrolysis by RIα: PDE termination complexes for adaptation to cAMP from GPCR hyperstimulation. Impairment of the signal termination process provides an alternate molecular basis for acrodysostosis.