Effectiveness analysis of deceleration capacity and traditional heart rate variability in diagnosing vasovagal syncope.

Background: Vasovagal syncope (VVS) is a prevalent medical condition with a lack of efficient methods for its detection. Aim: This study aimed to explore an objective clinical indicator in diagnosing VVS. Methods: The retrospective analysis involved clinical data of 243 syncope patients from 1 June 2020 to 31 July 2023. Among them, 108 patients had a negative result in the tilt test (TTT), while the remaining 135 patients had a positive result in the TTT. Relevant statistical methods were utilized to examine the correlation between VVS and different indicators of heart rate variability. Results: After screening, 354 patients being considered for VVS were evaluated, resulting in a final sample size of 243. Sex, age, deceleration capacity (DC), and standard deviation of all normal-to-normal intervals (SDNNs) were the variables that showed statistical significance between the TTT(-) group and the TTT(+) group. Independent risk factors identified by multivariate logistic regression were DC [odds ratio (OR) 1.710, 95% confidence interval (CI) 1.388-2.106, P < 0.001] and SDNN (OR 1.033, 95% CI 1.018-1.049, P < 0.001). Comparing the groups, receiver operating characteristic analysis revealed a notable distinction in both DC and SDNN [the respective areas under the curve were 0.789 (95% CI 0.730-0.848) and 0.702 (95% CI 0.637-0.767); the cutoff values were 7.15 and 131.42; P < 0.001, respectively]. Conclusion: In summary, DC can function as an impartial and easily accessible clinical marker for differentiating VVS. A value exceeding 7.15 ms might suggest a higher likelihood of syncope.

Monitoring of Isothermal Crystallization and Time-Temperature Transformation of Amorphous Felodipine: The Time-Domain Nuclear Magnetic Resonance Method.

The isothermal crystallization process of felodipine has been investigated using the time-domain Nuclear Magnetic Resonance (NMR) method for amorphous bulk and ground samples. The obtained induction and crystallization times were then used to construct the time-temperature-transformation (TTT) diagram, both above and below the glass transition temperature (Tg). The Nose temperature was found equal to 363 K. Furthermore, the dynamics of crystalline and amorphous felodipine were compared across varying temperatures. Molecular dynamics simulations were also employed to explore the hydrogen-bond interactions and dynamic properties of both systems.

Maturation and Assembly of mTOR Complexes by the HSP90-R2TP-TTT Chaperone System: Molecular Insights and Mechanisms.

The mechanistic target of rapamycin (mTOR) is a master regulator of cell growth and metabolism, integrating environmental signals to regulate anabolic and catabolic processes, regulating lipid synthesis, growth factor-induced cell proliferation, cell survival, and migration. These activities are performed as part of two distinct complexes, mTORC1 and mTORC2, each with specific roles. mTORC1 and mTORC2 are elaborated dimeric structures formed by the interaction of mTOR with specific partners. mTOR functions only as part of these large complexes, but their assembly and activation require a dedicated and sophisticated chaperone system. mTOR folding and assembly are temporarily separated with the TELO2-TTI1-TTI2 (TTT) complex assisting the cotranslational folding of mTOR into a native conformation. Matured mTOR is then transferred to the R2TP complex for assembly of active mTORC1 and mTORC2 complexes. R2TP works in concert with the HSP90 chaperone to promote the incorporation of additional subunits to mTOR and dimerization. This review summarizes our current knowledge on how the HSP90-R2TP-TTT chaperone system facilitates the maturation and assembly of active mTORC1 and mTORC2 complexes, discussing interactions, structures, and mechanisms.

Correlation analysis of patients with diabetic foot ulcers treated with tibial cortex transverse transport surgery and platelet-to-lymphocyte ratio and monocyte-to-neutrophil ratio.

BACKGROUND: Diabetic foot ulcers (DFUs) represent one of the most severe late-stage complications of diabetes. Tibial cortex transverse transport (TTT) surgery stands as the prevailing method for addressing DFUs. This surgical intervention holds the promise of expediting DFU wound healing and diminishing the rate of amputations, with the mitigation of inflammatory responses playing a pivotal role. In this study, we aim to explore the correlation between inflammation and TTT surgery, with the overarching goal of facilitating swift prognostic assessments in clinical practice. OBJECTIVES: The correlation between the severity of DFUs and clinical test results remains ambiguous. A clinical prediction model was devised to explore the connection between DFU severity and the efficacy of TTT surgery, utilizing straightforward and efficient clinical indicators. MATERIAL AND METHODS: Clinical data and examination results were gathered by tracking hospitalized DFU patients who underwent TTT surgery at the First Affiliated Hospital of Guangxi Medical University (Nanning, China). Indicators associated with DFU severity and wound healing time post-surgery were identified through logistic regression and least absolute shrinkage and selection operator (LASSO) regression analyses. Subsequently, a clinical prediction model was constructed. Finally, the intersection of these 2 sets of indicators revealed factors correlated with wound severity and post-operative healing duration. RESULTS: Our study was comprised of 202 patients who were categorized into 2 groups based on Wagner's grading classifications. Utilizing Student's t-tests, LASSO regression and logistic regression analyses, we identified 3 factors indicative of DFU severity: platelet-to-lymphocyte ratio (PLR), mixed lymphocyte reaction (MLR) and hemoglobin (HGB). Univariate COX regression analysis revealed 12 factors such as: white blood cells (WBC), neutrophils (NEUT), monocytes (MO), PLR, MLR, neutrophil-to-lymphocyte ratio (NLR), erythrocyte sedimentation rate (ESR), age, lymphocytes (LY), monocyte-to-neutrophil ratio (MNR), uric acid (UA), and albumin (ALB) associated with the postoperative healing duration. Ultimately, we identified 2 factors, PLR and MNR, at the intersection of these 2 datasets. CONCLUSIONS: Platelet-to-lymphocyte ratio and MNR were identified as factors associated with both the severity of DFUs and the prognosis following TTT surgery.

Biomechanical evaluation of a fixation technique with a modified hemicerclage for tibial tuberosity transposition: an ex vivo cadaveric study.

Objectives: (1) To determine stiffness, load at failure, and mode of failure of a novel fixation method with a tension modified-hemicerclage (MH) for tibial tuberosity transposition, and (2) to compare the biomechanical properties of this novel fixation technique to 2 pins (2Pins) and 2 pins and tension band wire fixation (2Pins + TBW). Study design: Thirty cadaveric stifles from dogs between 5.2 and 13.1 kg were assigned to 3 treatment groups: Group 1: fixation technique with MH; Group 2: 2Pins; Group 3: 2Pins + TBW. Biomechanical testing was performed with the tibia positioned at an angle of 135° relative to vertical position. Tensile force was applied to the patellar ligament until catastrophic failure was observed. The mode of failure, the load at failure, and the stiffness were compared among treatment groups. Results: The mean stiffness of the novel fixation (38.1 N/mm ± 7.1) and the 2Pins + TBW (40.2 N/mm ± 9.3) were greater than the 2Pins (26.7 N/mm ± 6.7). There was no significant difference between the novel fixation technique and 2Pins + TBW in stiffness and maximum load to failure. The 2Pins (284.3 N ± 70.5) failed at a significantly lower load than the tension modified-hemicerclage (555.7 N ± 225.9 N) and 2Pins + TBW (715.3 N ± 339.8 N). Conclusion: A fixation technique using a modified hemicerclage had the same strength and stiffness as the 2Pins + TBW and was stronger and stiffer than the 2 Pins technique in a cadaveric model.

In Situ Monitoring of the Curing of Highly Filled Epoxy Molding Compounds: The Influence of Reaction Type and Silica Content on Cure Kinetic Models.

Monitoring of molding processes is one of the most challenging future tasks in polymer processing. In this work, the in situ monitoring of the curing behavior of highly filled EMCs (silica filler content ranging from 73 to 83 wt%) and the effect of filler load on curing kinetics are investigated. Kinetic modelling using the Friedman approach was applied using real-time process data obtained from in situ DEA measurements, and these online kinetic models were compared with curing analysis data obtained from offline DSC measurements. For an autocatalytic fast-reacting material to be processed above the glass transition temperature Tg and for an autocatalytic slow-reacting material to be processed below Tg, time-temperature-transformation (TTT) diagrams were generated to investigate the reaction behavior regarding Tg progression. Incorporating a material containing a lower silica filler content of 10 wt% enabled analysis of the effects of filler content on sensor sensitivity and curing kinetics. Lower silica particle content (and a larger fraction of organic resin, respectively) favored reaction kinetics, resulting in a faster reaction towards Tg1. Kinetic analysis using DEA and DSC facilitated the development of highly accurate prediction models using the Friedman model-free approach. Lower silica particle content resulted in enhanced sensitivity of the analytical method, leading, in turn, to more precise prediction models for the degree of cure.

Burnout in healthcare - the Emperor's New Clothes.

Burnout is common among physicians; it severely alters their health and has a negative impact on functioning of healthcare systems. Hypertension, increased cortisol levels, maladaptive behaviors with negative social consequences, and suboptimal quality of care have been associated with healthcare providers' burnout. As the number of patients with cancers, psychiatric and neurodegenerative disorders will rise, we need new solutions to maintain physicians' health and, therefore, quality of care. Coping strategies before the COVID-19 pandemic seem ineffective in scaling all the deficits of the global healthcare systems. Examples of new initiatives include new collaborative projects, such as COH-FIT (The Collaborative Outcomes study on Health and Functioning during Infection Times - https://www.coh-fit.com), which aims to collect global data and understand the impact of the COVID-19 pandemic on physical and mental health in order to identify various coping strategies for patients and healthcare workers during infection times, or MEMO (Minimizing Error, Maximizing Outcome), funded by the Agency of Healthcare Research and Quality (AHRQ). Others: i) Rome Foundation GastroPsych undertake efforts dedicated to the science and practice of psychogastroenterology, a burgeoning field with roots in behavioral intervention, cognitive science and experimental psychology focused on fostering the professional growth and collaboration of those engaged in medical practices, or ii) World Gastroenterology Organisation (WGO), Train The Trainers (TTT) program including a new topic of the impact of burnout on career longevity in order to foster strategies for staying healthy and increasing career satisfaction. There is a need for continuous development of digital technologies (e.g. training simulators, telemedicine, robots and artificial intelligence). Their implementation into medical practice is inevitable. Now more than ever, there is a need for a new spirit in healthcare. Together with others in the field, we believe this article is a desperate call for maximizing the use of novel technologies supported by collaborative interactions among healthcare providers and medical professionals of diverse medical fields.

Exploring the Limits of High-Tg Epoxy Vitrimers Produced through Resin-Transfer Molding.

Over the past few years, scientists have developed new ways to overcome the recycling issues of conventional thermosets with the introduction of associative covalent adaptable networks (i.e., vitrimers) in polymer materials. Even though various end-use vitrimers have already been reported, just a few of them have targeted high-performance industrial applications. Herein, we develop a promising high-performance epoxy vitrimer based on a commercially available resin widely used in aeronautics with the highest glass transition temperature (Tg) of 233 °C ever reported for a vitrimer. A complete study of its physicochemical properties and cure kinetics was conducted, enabling the construction of the first time-temperature-transformation (TTT) diagram reported in the literature. This diagram allows a full determination of the processing and curing parameters leading to the manufacturing of vitrimer samples by the resin-transfer molding (RTM) process. The reshapability and limits therefrom of this high-Tg vitrimer were evaluated by three successful thermoforming cycles without degradation.

Genome-scale mapping of DNA damage suppressors through phenotypic CRISPR-Cas9 screens.

To maintain genome integrity, cells must accurately duplicate their genome and repair DNA lesions when they occur. To uncover genes that suppress DNA damage in human cells, we undertook flow-cytometry-based CRISPR-Cas9 screens that monitored DNA damage. We identified 160 genes whose mutation caused spontaneous DNA damage, a list enriched in essential genes, highlighting the importance of genomic integrity for cellular fitness. We also identified 227 genes whose mutation caused DNA damage in replication-perturbed cells. Among the genes characterized, we discovered that deoxyribose-phosphate aldolase DERA suppresses DNA damage caused by cytarabine (Ara-C) and that GNB1L, a gene implicated in 22q11.2 syndrome, promotes biogenesis of ATR and related phosphatidylinositol 3-kinase-related kinases (PIKKs). These results implicate defective PIKK biogenesis as a cause of some phenotypes associated with 22q11.2 syndrome. The phenotypic mapping of genes that suppress DNA damage therefore provides a rich resource to probe the cellular pathways that influence genome maintenance.

An Adaptive TTT Handover (ATH) Mechanism for Dual Connectivity (5G mmWave-LTE Advanced) during Unpredictable Wireless Channel Behavior.

Fifth Generation (5G) signals using the millimeter wave (mmWave) spectrums are highly vulnerable to blockage due to rapid variations in channel link quality. This can cause the devices or User Equipment (UE) to suffer from connection failure. In a dual connectivity (DC) network, the channel's intermittency issues were partially solved by maintaining the UE's connectivity to primary (LTE advanced stations) and secondary (5G mmWave stations) simultaneously. Even though the dual-connected network performs excellently in maintaining connectivity, its performance drops significantly due to the inefficient handover from one 5G mmWave station to another. The situation worsens when UE travels a long distance in a highly dense obstacle environment, which requires multiple ineffective handovers that eventually lead to performance degradation. This research aimed to propose an Adaptive TTT Handover (ATH) mechanism that deals with unpredictable 5G mmWave wireless channel behaviors that are highly intermittent. An adaptive algorithm was developed to automatically adjust the handover control parameters, such as Time-to-Trigger (TTT), based on the current state of channel condition measured by the Signal-to-Interference-Noise Ratio (SINR). The developed algorithm was tested under a 5G mmWave statistical channel model to represent a time-varying channel matrix that includes fading and the Doppler effect. The performance of the proposed handover mechanism was analyzed and evaluated in terms of handover probability, latency, and throughput by using the Network Simulator 3 tool. The comparative simulation result shows that the proposed adaptive handover mechanism performs excellently compared to conventional handovers and other enhancement techniques.

TTT (Tel2-Tti1-Tti2) Complex, the Co-Chaperone of PIKKs and a Potential Target for Cancer Chemotherapy.

The heterotrimeric Tel2-Tti1-Tti2 or TTT complex is essential for cell viability and highly observed in eukaryotes. As the co-chaperone of ATR, ATM, DNA-PKcs, mTOR, SMG1, and TRRAP, the phosphatidylinositol 3-kinase-related kinases (PIKKs) and a group of large proteins of 300-500 kDa, the TTT plays crucial roles in genome stability, cell proliferation, telomere maintenance, and aging. Most of the protein kinases in the kinome are targeted by co-chaperone Cdc37 for proper folding and stability. Like Cdc37, accumulating evidence has established the mechanism by which the TTT interacts with chaperone Hsp90 via R2TP (Rvb1-Rvb2-Tah1-Pih1) complex or other proteins for co-translational maturation of the PIKKs. Recent structural studies have revealed the α-solenoid structure of the TTT and its interactions with the R2TP complex, which shed new light on the co-chaperone mechanism and provide new research opportunities. A series of mutations of the TTT have been identified that cause disease syndrome with neurodevelopmental defects, and misregulation of the TTT has been shown to contribute to myeloma, colorectal, and non-small-cell lung cancers. Surprisingly, Tel2 in the TTT complex has recently been found to be a target of ivermectin, an antiparasitic drug that has been used by millions of patients. This discovery provides mechanistic insight into the anti-cancer effect of ivermectin and thus promotes the repurposing of this Nobel-prize-winning medicine for cancer chemotherapy. Here, we briefly review the discovery of the TTT complex, discuss the recent studies, and describe the perspectives for future investigation.

Controlling the Thermal Stability of a Bainitic Structure by Alloy Design and Isothermal Heat Treatment.

The aim of this work was to develop a novel bainitic steel that will be specifically dedicated to achieving a high degree of refinement (nano- or submicron scale) along with increased thermal stability of the structure at elevated temperatures. The material was characterized by improved in-use properties, expressed as the thermal stability of the structure, compared to nanocrystalline bainitic steels with a limited fraction of carbide precipitations. Assumed criteria for the expected low martensite start temperature, bainitic hardenability level, and thermal stability are specified. The steel design process and complete characteristics of the novel steel including continuous cooling transformation and time-temperature-transformation diagrams based on dilatometry are presented. Moreover, the influence of bainite transformation temperature on the degree of structure refinement and dimensions of austenite blocks was also determined. It was assessed whether, in medium-carbon steels, it is possible to achieve a nanoscale bainitic structure. Finally, the effectiveness of the applied strategy for enhancing thermal stability at elevated temperatures was analyzed.

Train the Trainer in Bleeding Control: A Two-Year Pilot Study in Low-Income and Middle-Income Countries.

INTRODUCTION: Traumatic hemorrhage represents a major cause of mortality in low-income and middle-income countries (LMICs). Thus, LMICs can benefit from improvements to prehospital hemorrhage management. One strategy is implementation of a bleeding control course using the "train the trainer" model (TTT) to increase course availability. The Stop the Bleed (STB) campaign provides laypeople with basic knowledge and skills of hemorrhage control. While the feasibility and success of the STB course have been demonstrated in the United States, course dissemination in LMICs has been slower and its feasibility using the TTT model has not been established. MATERIALS AND METHODS: From December 2017 to January 2019, instructors from the International Surgical Health Initiative conducted seven surgical humanitarian trips and taught 10 index 1-h STB training sessions across six LMICs. LMIC instructors were encouraged to continue providing STB courses following departure of the visiting instructors. Course data were collected from sign-in sheets and analyzed using Microsoft Excel. RESULTS: Ten index courses conducted by United States-trained STB experts trained 35 LMIC instructors over 2 y. Six of 35 offered 12 additional courses, certifying 323 new trainees, an 823% increase from the initial cohort. Overall, implementation of the TTT model yielded 22 STB courses in six LMICs, producing 358 new trainees. CONCLUSIONS: This pilot study shows the STB TTT model was feasible and effective in expanding bleeding control trainer capacity in four of six LMICs. Use of the TTT model in LMICs may represent a means to increase STB course availability and is one strategy to improve prehospital hemorrhage control in LMICs.

Study on Quench Sensitivity during Isothermal Treatment of 7A65 Aluminum Alloy.

The quenching sensitivity of 7A65 aluminum alloy was investigated using interrupted quenching experiments. The time-temperature transformation (TTT) and time-temperature performance (TTP) curves of the alloy were determined. The results indicate that the nose temperature is about 320 °C and the quenching sensitivity temperature range is from 240 °C to 360 °C. During the isothermal treatment, the supersaturated solid solution resolves to the equilibrium phase of η (MgZn2), and the precipitation rate is the largest at about 320 °C. Through transmission electron microscope (TEM) observation and X-ray diffraction (XRD) tests, it was found that with the extension of the isothermal holding time, the originally dispersed η' phase gradually decreases until disappear, and the number of η phase increases and gradually grows up at the grain boundary or around the Al3Zr particles. The rod-like η phase at the grain boundary is distributed from discontinuous distribution to chain-like continuous distribution, and the precipitation free zone (PFZ) is gradually generated and widened as the holding time is extended. At the nose temperature, the driving force of nucleation is high, and the diffusion rate is fast, which promotes the precipitation and growth of η phases. The coarse η phase weakens the mechanical properties. According to the results, it is recommended to increase the cooling rate at the sensitivity temperature range to reduce the precipitation of the η phase and decrease the quenching cooling rate from solution temperature to 360 °C to reduce residual stresses in the components.

Determination of TTT Diagrams of Ni-Al Binary Using Neural Networks.

The heat treatment of a metal is a set of heating and cooling cycles that a metal undergoes to change its microstructure and, therefore, its properties. Temperature-time-transformation (TTT) diagrams are an essential tool for interpreting the resulting microstructures after heat treatments. The present work describes a novel proposal to predict TTT diagrams of the γ' phase for the Ni-Al alloy using artificial neural networks (ANNs). The proposed methodology is composed of five stages: (1) database creation, (2) experimental design, (3) ANNs training, (4) ANNs validation, and (5) proposed models analysis. Two approaches were addressed, the first to predict only the nose point of the TTT diagrams and the second to predict the complete curve. Finally, the best models for each approach were merged to compose a more accurate hybrid model. The results show that the multilayer perceptron architecture is the most efficient and accurate compared to the simulated TTT diagrams. The prediction of the nose point and the complete curve showed an accuracy of 98.07% and 86.41%, respectively. The proposed final hybrid model achieves an accuracy of 96.59%.

The Role of Hsp90-R2TP in Macromolecular Complex Assembly and Stabilization.

Hsp90 is a ubiquitous molecular chaperone involved in many cell signaling pathways, and its interactions with specific chaperones and cochaperones determines which client proteins to fold. Hsp90 has been shown to be involved in the promotion and maintenance of proper protein complex assembly either alone or in association with other chaperones such as the R2TP chaperone complex. Hsp90-R2TP acts through several mechanisms, such as by controlling the transcription of protein complex subunits, stabilizing protein subcomplexes before their incorporation into the entire complex, and by recruiting adaptors that facilitate complex assembly. Despite its many roles in protein complex assembly, detailed mechanisms of how Hsp90-R2TP assembles protein complexes have yet to be determined, with most findings restricted to proteomic analyses and in vitro interactions. This review will discuss our current understanding of the function of Hsp90-R2TP in the assembly, stabilization, and activity of the following seven classes of protein complexes: L7Ae snoRNPs, spliceosome snRNPs, RNA polymerases, PIKKs, MRN, TSC, and axonemal dynein arms.

A Room-Temperature Surface Acoustic Wave Ammonia Sensor Based on rGO/DPP2T-TT Composite Films.

Surface acoustic wave (SAW) sensors based on reduced graphene oxide/poly (diketopyrrolopyrrolethiophene-thieno [3,2-b]thiophene-thiophene) (rGO/DPP2T-TT) composite sensing films for the detection of ammonia were investigated at room temperature in this study. The rGO/DPP2T-TT composite films were deposited onto ST-X quartz SAW resonators by a drop-casting method. FESEM, EDS, and XRD characterizations showed that the rGO/DPP2T-TT composite film was successfully synthesized and exhibited numerous wrinkles and a rough structure, which are crucial for gas adsorption. The frequency response to 500-1400 ppb ammonia shown by the prepared SAW sensor coated with rGO/DPP2T-TT composite film increased linearly as the ammonia concentration increased. The sensor based on a rGO/DPP2T-TT composite film exhibited a positive frequency shift of 55 Hz/ppm, and its frequency response to 500 ppb ammonia was 35 Hz. The sensors thus show promising potential in detecting sub-ppm concentration levels of NH3 at room temperature, which opens up possibilities for applications in the noninvasive detection of NH3 in the breath. As a result, the rGO/DPP2T-TT composite sensor can be a good candidate for in situ medical diagnosis and indoor/outdoor environment monitoring.

Palladium-103 plaque brachytherapy for retinoblastoma: Long term follow up.

Purpose: Radiation has been used in the treatment of retinoblastoma. Herein, we present the novel use of palladium-103 plaque brachytherapy as primary treatment. Observation: An 8-year-old asymptomatic girl presented was found to have a solitary peripheral retinoblastoma in her right eye. She was treated with primary palladium-103 plaque brachytherapy (47.4 Gray over 5 consecutive days). A secondary, vitreous hemorrhage noted 46 months after irradiation was successfully controlled by laser tumor-demarcation. With 19-years follow up, there has been no clinical scleropathy, or local tumor recurrence. The eye yields 20/20 vision and there has been no systemic metastasis. Conclusion and importance: Palladium-103 plaque brachytherapy successfully controlled retinoblastoma, while preserving the globe, vision, and life.

Construction of a TTT-η Diagram of High-Refractive Polyurethane Based on Curing Kinetics.

A time-temperature-transformation-viscosity (TTT-η) diagram can reflect changes in the physical states of a resin, which take on significance for the study of the curing process of polyurethane resin lenses. Coupling the differential scanning calorimetry (DSC) test, the curing kinetic parameters of 1,4-bis(isocyanatomethyl)cyclohexane (H6XDI)/2,3-bis((2-mercaptoethyl)thio)-1-propanethiol (BES) polyurethane system were obtained. By phenomenological modeling, the relationships between degree, temperature, and time were obtained. An isothermal DSC test was carried out at 423 K. Based on the DiBenedetto equation, the relationships between glass transition temperature, degree of cure, and time were obtained, and the glass transition temperature was thus correlated with temperature and time. The gelation time at different temperatures was measured by rotary rheometry, and the relationship between gelation time and gelation temperature was established. The time-temperature-transformation (TTT) diagram of H6XDI/BES system was constructed accordingly. Subsequently, a six-parameter double Arrhenius equation was used as the basis for the rheological study. The viscosity was examined during the curing process. The TTT-η diagram was obtained, which laid the theoretical foundation for the optimization and setting of processing parameters.

The Hsp90 cochaperone TTT promotes cotranslational maturation of PIKKs prior to complex assembly.

Phosphatidylinositol 3-kinase-related kinases (PIKKs) are a family of kinases that control fundamental processes, including cell growth, DNA damage repair, and gene expression. Although their regulation and activities are well characterized, little is known about how PIKKs fold and assemble into active complexes. Previous work has identified a heat shock protein 90 (Hsp90) cochaperone, the TTT complex, that specifically stabilizes PIKKs. Here, we describe a mechanism by which TTT promotes their de novo maturation in fission yeast. We show that TTT recognizes newly synthesized PIKKs during translation. Although PIKKs form multimeric complexes, we find that they do not engage in cotranslational assembly with their partners. Rather, our findings suggest a model by which TTT protects nascent PIKK polypeptides from misfolding and degradation because PIKKs acquire their native state after translation is terminated. Thus, PIKK maturation and assembly are temporally segregated, suggesting that the biogenesis of large complexes requires both dedicated chaperones and cotranslational interactions between subunits.