Accuracy of a local positioning system for time-series speed and acceleration and performance indicators in game sports.

The objective was to determine the reliability and validity of a local positioning system (LPS) promising high accuracy at reduced product costs. Fifty-five random static positions in a gym (54.8 × 26.0 m) were obtained 10 times via LPS (50 Hz) and measuring tape. An athlete's LPS-derived peak and time-series speed and acceleration during dynamic movements (n = 80) were compared with Vicon (100 Hz). Reliability and validity were assessed via Intraclass and Concordance Correlation Coefficients (ICC/CCC), root mean square errors, Bland-Altman plots, and analysis of variance. ICC3,1 (≥0.999) and CCC (0.387-0.999) were calculated for static positions (errors <0.22 m). CCC for time-series speed and acceleration, and peak speed, acceleration, and deceleration were 0.884-0.902, 0.777-0.854, 0.923, 0.486, and 0.731, respectively. Errors were larger in time-series acceleration (14.37 ± 3.77%) than in speed (11.99 ± 5.78%) (ηp2 = 0.472, p < 0.001) and in peak acceleration (28.04 ± 14.34%) and deceleration (25.07 ± 14.90%) than in speed (7.34 ± 6.07%) (ηp2 = 0.091, p < 0.01). LPS achieved excellent reliability and moderate-to-excellent validity of time-series speed and acceleration. The system accurately measured peak speed but not peak acceleration and deceleration. The system is suitable for analyses based on instantaneous speed and acceleration in game sports (e.g., energy estimations).

Sensor number in simplified insole layouts and the validity of ground reaction forces during locomotion.

Research attempted to validate simplified insoles with a reduced number of sensors to facilitate clinical application. However, the ideal sensor number is yet to be determined. The purpose was to investigate the validity of vertical ground reaction forces in various simplified pressure sensor insoles and to identify an optimal compromise between sensor number and measurement performance. A Kistler force plate (1000 Hz) and 99-sensor Pedar-X insole (100 Hz) obtained force data of 15 participants during walking and jogging. Eight simplified insole layouts (3-17 sensors) were simulated. Layout performances were expressed as Pearson's correlation coefficients (r) with force plate as reference and coefficient of variation. Differences were assessed via repeated-measures ANOVA as partial eta square (ηp2) at p < .05. All layouts correlated with the force plate (r = .70-.99, p < .01). All layout performances were higher in jogging than in walking by r = +.07 ± .04 (ηp2=.28-.66, p < .05). The three- and five-sensor layouts yielded the lowest correlation (r = .70-.88) and the highest coefficient of variation (11-22%). Layout performances improved constantly from 7 to 11 sensors. The optimal compromise between simplification and measurement performance, quantified via change in correlation per sensor number, was found in the 11-sensor layout, recommendable for practical settings to improve monitoring and adjusting protocols.

Ideal Combinations of Acceleration-Based Intensity Metrics and Sensor Positions to Monitor Exercise Intensity under Different Types of Sports.

This study quantified the strength of the relationship between the percentage of heart rate reserve (%HRR) and two acceleration-based intensity metrics (AIMs) at three sensor-positions during three sport types (running, basketball, and badminton) under three intensity conditions (locomotion speeds). Fourteen participants (age: 24.9 ± 2.4 years) wore a chest strap HR monitor and placed three accelerometers at the left wrist (non-dominant), trunk, and right shank, respectively. The %HRR and two different AIMs (Player Load per minute [PL/min] and mean amplitude deviation [MAD]) during exercise were calculated. During running, both AIMs at the shank and PL at the wrist had strong correlations (r = 0.777-0.778) with %HRR; while other combinations were negligible to moderate (r = 0.065-0.451). For basketball, both AIMs at the shank had stronger correlations (r = 0.604-0.628) with %HRR than at wrist (r = 0.536-0.603) and trunk (r = 0.403-0.463) with %HRR. During badminton exercise, both AIMs at shank had stronger correlations (r = 0.782-0.793) with %HRR than those at wrist (r = 0.587-0.621) and MAD at trunk (r = 0.608) and trunk (r = 0.314). Wearing the sensor on the shank is an ideal position for both AIMs to monitor external intensity in running, basketball, and badminton, while the wrist and using PL-derived AIM seems to be the second ideal combination.

Systemic Lactate Elevation Induced by Tobacco Smoking during Rest and Exercise Is Not Associated with Nicotine.

Lactate is a metabolite produced during anaerobic glycolysis for ATP resynthesis, which accumulates during hypoxia and muscle contraction. Tobacco smoking significantly increases blood lactate. Here we conducted a counter-balanced crossover study to examine whether this effect is associated with inhaling nicotine or burned carbon particles. Fifteen male smokers (aged 23 to 26 years) were randomized into 3 inhalation conditions: tobacco smoking, nicotine vaping, and nicotine-free vaping, conducted two days apart. An electronic thermal evaporator (e-cigarette) was used for vaping. We have observed an increased blood lactate (+62%, main effect: p < 0.01) and a decreased blood glucose (−12%, main effect: p < 0.05) during thermal air inhalations regardless of the content delivered. Exercise-induced lactate accumulation and shuttle run performance were similar for the 3 inhalation conditions. Tobacco smoking slightly increased the resting heart rate above the two vaping conditions (p < 0.05), implicating the role of burned carbon particles on sympathetic stimulation, independent of nicotine and thermal air. The exercise response in the heart rate was similar for the 3 conditions. The results of the study suggest that acute hypoxia was induced by breathing thermal air. This may explain the reciprocal increases in lactate and decreases in glucose. The impaired lung function in oxygen delivery of tobacco smoking is unrelated to nicotine.

The Validity and Reliability of a Tire Pressure-Based Power Meter for Indoor Cycling.

The purpose of this study was to evaluate the validity and reliability of a tire pressure sensor (TPS) cycling power meter against a gold standard (SRM) during indoor cycling. Twelve recreationally active participants completed eight trials of 90 s of cycling at different pedaling and gearing combinations on an indoor hybrid roller. Power output (PO) was simultaneously calculated via TPS and SRM. The analysis compared the paired 1 s PO and 1 min average PO per trial between devices. Agreement was assessed by correlation, linear regression, inferential statistics, effect size, and Bland-Altman LoA. Reliability was assessed by ICC and CV comparison. TPS showed near-perfect correlation with SRM in 1 s (rs = 0.97, p < 0.001) and 1-min data (rs = 0.99, p < 0.001). Differences in paired 1 s data were statistically significant (p = 0.04), but of a trivial magnitude (d = 0.05). There was no significant main effect for device (F(1,9) = 0.05, p = 0.83, ηp2 = 0.97) in 1 min data and no statistical differences between devices by trial in post hoc analysis (p < 0.01-0.98; d < 0.01-0.93). Bias and LoA were -0.21 ± 16.77 W for the 1 min data. Mean TPS bias ranged from 3.37% to 7.81% of the measured SRM mean PO per trial. Linear regression SEE was 7.55 W for 1 min TPS prediction of SRM. ICC3,1 across trials was 0.96. No statistical difference (p = 0.09-0.11) in TPS CV (3.6-5.0%) and SRM CV (4.3-4.7%). The TPS is a valid and reliable power meter for estimating average indoor PO for time periods equal to or greater than 1 min and may have acceptable sensitivity to detect changes under less stringent criteria (±5%).

Multi-national perceptions on challenges, opportunities, and support structures for Dual Career migrations in European student-athletes.

Despite Dual Careers (sports and education) and mobility of students being priorities in the funding policies of the European Commission, migrating student-athletes report severe challenges and decreased performance or dropouts at sport and academic levels. The objective of this study was to depict and assess the perceptions on challenges, support services, and their effectiveness in consideration of specific characteristics of participants and migrations. Based on a meta-synthesis and previous findings, a 50-items questionnaire was developed and completed by 245 student-athletes in 5 European countries. Participants with Dual Careers migration experience (n = 140) were considered for analyses of qualitative and quantitative (ordinal 5pt-Likert-scaled and metric) data on the Dual Career status, migration characteristics, received services, and outcomes. Chi-square-tests were conducted for differences between countries and genders at a significance level of p < .05. Country-related differences were found for experiences and intentions to migrate (X2(12) = 50.52, p<0.001), duration of the migration (X2(16) = 38.20, p = 0.001), financial support (X2(8) = 29.87, p<0.001), and decreased performances in academics (X2(16) = 56.12, p<0.001) and sports (X2(16) = 31.79, p = 0.01). Gender-related difference emerged in financial support (X2(4) = 10.68, p = 0.03), duration of the migration (X2(4) = 14.56, p = 0.01), and decreased academic performance (X2(4) = 10.57, p = 0.03). Tutoring and counselling support was ranked as the most effective support, especially when received from the academic field (4.0±1.0 pt) and others (4.1±0.8 pt), followed by online services from sport and academic sectors (both: 3.9±0.9 pt). Considering the pervasive globalization of sport and education, Dual Career migration can contribute to the development of a European sport culture. The high ratio of migrating student-athletes underlines the relevance of migrations in the field of Dual Careers. This study contributes to the literature by adding insights on practices, challenges, supports, and outcomes perceived by student-athletes migrating in Europe. Moreover, country- and gender-related differences support the consideration of specific characteristics and reveal critical factors in specific target groups. The findings contribute to identifying requirements and effective support measures in Dual Career migrations and can be used to improve support services.

A novel approach to measuring wobble board performance in individuals with chronic ankle instability.

Computerized wobble boards (WB) are used to objectively assess balance in healthy and chronic ankle instability individuals. As in field setting health professionals might not own WB, objective evaluations are not always feasible. Therefore, the aim of this tudy was to investigate the contribution of sagittal plane joints angular-displacement and anthropometrics to predict equations to estimate WB performance by portable two-dimensional motion analysis (2D-MA) and cross-validate the developed equations in chronic ankle instability individuals. Thirty-nine healthy and twenty chronic ankle instability individuals stood on a WB in single stance position. The balance test consisted of three 30s trials per limb keeping the platform flat at 0°. Trials were video recorded, and three time-segments joints angular-displacement analyzed with 2D-MA: segment 1 (T1) including 30s data, segment 2 (T2) from second 0 to 10, segment 3 (T3) only the first 5s. Mixed regression for multilevel models was used to estimate WB performance for each time-segment and to examine limb differences for the predicted WB performance in chronic ankle instability sample. The accuracy of the equations to detect injured limbs was calculated via area under the curve for receiver operating characteristic. Ankle and knee angular-displacement parameters, body height and lower limb length were the major predictors of WB performance for the extrapolated models (p < 0.05; R2 = 0.83-0.56). The measured WB performance and T1 model showed significant (p < 0.05) performance differences between the injured and uninjured limbs. Receiver operating characteristic analysis showed an asymptotic significance of 0.03 for T1 equation with area under the curve of 0.70. The proposed models provide different methods to quantify the performance and accurately detect the injured limb in individuals with unilateral chronic ankle instability, when measuring balance via WB might not be feasible. App-makers may use the equations to provide an automatic all-in-one system to monitor the performance status and progress.

Effect of Differential Training on Female Volleyball Spike-Jump Technique and Performance.

PURPOSE: To determine the effect of in-season differential training on volleyball spike-jump technique and performance in elite-level female players. METHODS: During the season, spike jumps of 12 elite female players (Austrian Volleyball League Women) were recorded by 13 Qualisys Oqus cameras (250 Hz) and an AMTI force plate (1000 Hz). First measurement was made at the beginning of the investigation. Two identical measurements were repeated after a first and a second interval. The first interval served as control phase. The second interval was comparable in length and regular program but included differential training (6 wk, 8 sessions of 15-20 min) as a modified warm-up. It addressed specific performance determinants. Analyses of variances were calculated for the 3 measurements and for the development during control and intervention phase. RESULTS: Initial jump height (0.44 [0.09] m) changed by -4.5% during the control phase and +11.9% during the intervention (P < .001, ηp2=.70). All approach variables, arm backswing, and velocity-conversion strategy improved compared with the control phase (Δ%: 6.1-51.2%, P < .05, ηp2=.40-.80). Joint angles, countermovement depth, maximal angular velocities, and torso incline were not affected (Δ%: -2.9-9.1%, P = .066-.969, ηp2=.00-.27). CONCLUSIONS: In-season differential training led to technical adaptations and increased spike-jump height in elite female players. The differential training program allowed players to experience a range of adaptability and to adjust toward an individual optimum in technical components of performance determinants. Coaches are encouraged to apply technical differential training to elite athletes and to target biomechanical performance factors specifically.

Dynamic Balance Evaluation: Reliability and Validity of a Computerized Wobble Board.

Fusco, A, Giancotti, GF, Fuchs, PX, Wagner, H, Varalda, C, Capranica, L, and Cortis, C. Dynamic balance evaluation: reliability and validity of a computerized wobble board. J Strength Cond Res 34(6): 1709-1715, 2020-Computerized wobble boards (WBs) are inexpensive, transportable, and user-friendly devices to objectively quantify the dynamic balance performances out of laboratory settings, although it has not been established if they are reliable and valid tools. Therefore, the purpose of this study was to determine the reliability and validity of a computerized WB. Thirty-nine (18 females and 21 males) young adults (age: 23.3 ± 2.1 years; body mass: 65.9 ± 1.8 kg; height: 168.2 ± 8.8 cm; leg length: 78.8 ± 5.7 cm; and body mass index: 23.2 ± 2.1 kg·m) participated in the study. Subjects were assessed during 3 separate sessions on different days with a 48-hour rest in between. A total number of 2 WB single limb tests and 1 Y Balance Test (YBT) were performed. The WB performance was registered using the proprietary software and represented by the time spent in the target zone, which represented the 0° tilt angle measured by the triaxial accelerometer in the WB. YBT normalized reach distances were recorded for the anterior, posteromedial, and posterolateral directions. Intraclass correlation coefficient, 95% confidence interval, SEM, minimal detectable change, and Bland-Altman plots were used to evaluate intrasession and intersession reliability, whereas Pearson product moment correlation was used to determine concurrent validity. Reliability ranged from fair to excellent, showing acceptable levels of error and low minimal detectable change. However, all correlation coefficients between WB and YBT outcomes were poor. Despite the 2 methods addressing different aspects of balance performance, WB seems to validly serve its purpose and showed good reliability. Therefore, computerized WBs have the potential to become essential devices for dynamic balance assessment.

Y balance test: Are we doing it right?

OBJECTIVES: The multifaceted characteristic and task-specificity of postural control clearly reflects the need of knowing which factors could influence the balance measures in order to provide reliable and unbiased information. Therefore, this study aimed to investigate the effects of selected anthropometric characteristics, sex, lower limb's strength and dominance on the Y balance test (YBT). DESIGN: Descriptive laboratory study. METHODS: Forty-two young adults performed the YBT. The raw and normalized reach distances values were recorded. ANOVA was used to examine differences between sex and limb dominance, whereas multiple linear regression models were built to identify variables associated with better postural control. RESULTS: No significant sex differences were observed, except for the normalized anterior direction (p=0.0324). No significant differences between limbs emerged. Regression models significantly explained between 8-49% of the variance. Trunk length, strength, and the interaction between sex with strength were the major predictors of the raw measures. Unexpectedly, lower limb length explained only 0.08% of the raw anterior direction variance. Strength and its interaction with sex were positively associated with normalized measures. Surprisingly, the relative lower limb length variable was negatively associated with the normalized measures. Each % point increase in relative lower limb length was associated with a decrease in normalized performance ranging from 1.73 to 4.91%. CONCLUSIONS: Anthropometric characteristics, sex and lower limb strength differently influenced the YBT measures, regardless of limb dominance. Consequently, these variables should be controlled to limit the variability for an accurate evaluation of postural balance, especially if different YBT measures are used.

Spike jump biomechanics in male versus female elite volleyball players.

There are well-known biological differences between women and men, especially in technical-coordinative variations that contribute to sex differences in performance of complex movements like the most important offensive action in volleyball, the spike jump. The aim of this study was to investigate sex-dependent performance and biomechanical characteristics in the volleyball spike jump. Thirty female and male sub-elite volleyball players were analysed while striking a stationary ball with maximal spike jump height. Twelve MX13 Vicon cameras with a cluster marker set, two AMTI force plates, surface EMG, and a Full-Body 3D model in Visual3D were used. Main findings include sex differences (P< .05) in jump height (pη2 = .73), approach [speed (pη2 = .61), step length], transition strategy [plant angle, neuromuscular activation (pη2 = .91), horizontal force maxima and impulses], acceleration distances [centre of mass displacement (pη2 = .21), minimal knee and hip angles], use of torso and arms [incline, angular velocity (pη2 = .23)]. Correlations support that the results cannot be explained fully by strength and power differences between sexes but represent the product of technical-coordinative variations. Their relevance is acknowledged for both sexes and numerous performance determinants displayed sex differences. The integration of such attributes into sex-specific training seems promising but its effect requires further investigation.

Movement characteristics of volleyball spike jump performance in females.

OBJECTIVES: Performance factors in the volleyball spike jump are well known for male players; however, technical-coordinative differences for female players are known only marginally. The objective of this study was to investigate the relationship between movement characteristics and female' spike jump performance and to identify the most relevant aspects of jump height and ball velocity. DESIGN: Single group correlation and regression. METHODS: Fifteen elite female volleyball players performed spike jumps by striking a stationary ball at maximal jump height. Data were collected via twelve MX13 Vicon cameras (250Hz), two AMTI force plates (2000Hz), and controlled via Visual3D software. RESULTS: Ten out of 42 characteristics correlated with jump height and none of 22 correlated with ball velocity. A stepwise regression model (adjusted R2=0.82, p<0.001) predicted jump height based on orientation step length and maximal angular velocity of dominant knee extension. For ball velocity, stepwise regression analysis was not feasible; however, an alternative model yielded adjusted R2=0.55, p<0.01. CONCLUSIONS: Key aspects for jump height were (1) optimised approach and energy conversion, (2) wide dynamic arm swing allowing for a forceful countermovement and, thus, increased range of motion in lower limbs, and (3) large angular velocities in ankles and knees, especially on the dominant side. These aspects strongly determined jump height in females and should be included in technical and strength-related training. For ball velocity, upper body anthropometrics and angular joint velocities emerged as the most important criteria. The importance of specific joints may depend on variations in striking technique.

Physical Performance in Elite Male and Female Team-Handball Players.

PURPOSE: Biological differences between men and women are well known; however, literature addressing knowledge about the influence of sex on specific and general performance in team handball is almost nonexistent. Consequently, the aim of the study was to assess and compare specific and general physical performance in male and female elite team-handball players, to determine if the differences are consequential for general compared with specific physical performance characteristics and the relationship between general and specific physical performance. METHODS: Twelve male and 10 female elite team-handball players performed a game-based performance test, upper- and lower-body strength and power tests, a sprinting test, and an incremental treadmill running test. RESULTS: Significant differences (P < .05) between male and female players were found for peak oxygen uptake and total running time during the treadmill test, 30-m sprinting time, leg-extension strength, trunk- and shoulder-rotation torque, and countermovement-jump height, as well as offense and defense time, ball velocity, and jump height in the game-based performance test. An interaction (sex × test) was found for time and oxygen uptake, and except shoulder-rotation torque and ball velocity in women, the authors found only a low relationship between specific and general physical performance. CONCLUSION: The results of the study revealed that male players are heavier, taller, faster, and stronger; jump higher; and have better aerobic performance. However, female players performed relatively better in the team-handball-specific tests than in the general tests. The findings also suggest that female players should focus more on strength training.

Wobble board balance assessment in subjects with chronic ankle instability.

BACKGROUND: Wobble boards (WBs), commonly used to train postural control, have been recently equipped with accelerometers connected to a computer displaying real-time balance performances. However, little is known about their ability to detect balance deficits in subjects with unilateral chronic ankle instability (CAI). OBJECTIVE: To determine if computerized WBs can detect balance deficits in subjects with unilateral CAI. METHODS: Fifteen subjects with unilateral CAI and fifteen uninjured subjects performed one WB test and one Y Balance Test (YBT) during two separate randomized sessions. WB performance was assessed as the time (s) spent on the platform by keeping it flat at 0° during three 30-s trials for each limb. Normalized (%) reach distances values for anterior, posteromedial, posterolateral directions and composite were recorded for YBT. RESULTS: WB has been shown to be a reliable and accurate device for detecting balance deficits between and within subjects with unilateral CAI. The area under the curve for receiver operating characteristic was 0.80 (asymptotic significance 0.001), suggesting that WBs have the capability to accurately discriminate between injured and uninjured limbs. SIGNIFICANCE: Computerized WBs can fill the gap caused by limitations between subjective-based clinical assessment and laboratory-based testing, especially in field-based settings, where specificity, transportability and time constraints are crucial. The results of the present study suggest that WBs may facilitate the detection of balance impairments in subjects with unilateral CAI, without complexity in its use or data interpretation.

Specific physiological and biomechanical performance in elite, sub-elite and in non-elite male team handball players.

BACKGROUND: Team handball is a dynamic sport game that is played professionally in numerous countries. However, knowledge about training and competition is based mostly on practical experience due to limited scientific studies. Consequently, the aims of our study were to compare specific physiological and biomechanical performance in elite, sub-elite and in non-elite male team handball players. METHODS: Thirty-six elite, sub-elite and non-elite male team handball players performed a game based performance test, upper-body and lower-body strength tests, 30-m sprint test, counter movement jump test and an incremental treadmill running test. RESULTS: Significant differences (P<0.05) were found for the peak oxygen uptake, heart rate, offense and defense time, jump height and ball velocity during the jump throw in the game based performance test, maximal oxygen uptake in the incremental treadmill running test as well as in maximal leg strength and leg explosive strength in the isometric strength test. CONCLUSIONS: Elite male players have an enhanced specific agility, a better throwing performance, a higher team handball specific oxygen uptake and higher leg strength compared to sub-elite and non-elite players. Based on these results we recommend that training in team handball should focus on game based training methods to improve performance in specific agility, endurance and technique.

Kinematic analysis of proximal-to-distal and simultaneous motion sequencing of straight punches.

Consecutive proximal-to-distal sequencing of motion is considered to be integral for generating high velocity of distal segments in many sports. Simultaneous usage of proximal and distal segments as seen in martial arts is by far less well investigated. Therefore, the aim of the study was to characterise and differentiate the concepts of consecutive (CSM) and simultaneous (SSM) sequence of motion in straight reverse punches as practised in Practical Wing Chun. Four experienced martial artists succeeded an eligibility test for technical proficiency in both concepts and performed a total number of 20 straight punches per concept. Eight MX13 Vicon cameras (250 fps) and Visual3D were used for motion capture and analyses. Both motion concepts showed proximal-to-distal sequencing of maximal joint velocities but, in SSM, this was coupled with simultaneous initiation. Key characteristics were: high pelvis momentum and backswing of shoulder and elbow (CSM); and importance of shoulder involvement (SSM). Different ranges of motion, timing aspects and achieved maximal angular velocities distinguished both concepts, which led to differences (p < 0.05) in fist velocity at contact, execution time, distance and horizontal shift of the centre of mass. Proper application of both concepts depends on the environmental setting, situational requirements and individual fighting style.

Antitumor agent 25-epi Ritterostatin GN1N induces endoplasmic reticulum stress and autophagy mediated cell death in melanoma cells.

Metastatic melanoma is the most aggressive of all skin cancers and is associated with poor prognosis owing to lack of effective treatments. 25-epi Ritterostatin GN1N is a novel antitumor agent with yet undefined mechanisms of action. We sought to delineate the antitumor mechanisms of 25-epi Ritterostatin GN1N in melanoma cells to determine the potential of this compound as a treatment for melanoma. Activation of the endoplasmic reticulum (ER) stress protein glucose-regulated protein 78 (GRP78) has been associated with increased melanoma progression, oncogenic signaling, drug resistance, and suppression of cell death. We found that 25-epi Ritterostatin GN1N induced cell death in melanoma cells at nanomolar concentrations, and this cell death was characterized by inhibition of GRP78 expression, increased expression of the ER stress marker CHOP, loss of mitochondrial membrane potential, and lipidation of the autophagy marker protein LC3B. Importantly, normal melanocytes exhibited limited sensitivity to 25-epi Ritterostatin GN1N. Subsequent in vivo results demonstrated that 25-epi Ritterostatin GN1N reduced melanoma growth in mouse tumor xenografts and did not affect body weight, suggesting minimal toxicity. In summary, our findings indicate that 25-epi Ritterostatin GN1N causes ER stress and massive autophagy, leading to collapse of mitochondrial membrane potential and cell death in melanoma cells, with minimal effects in normal melanocytes. Thus, 25-epi Ritterostatin GN1N is a promising anticancer agent that warrants further investigation.

Ritterostatin GN 1N , a Cephalostatin-Ritterazine Bis-steroidal Pyrazine Hybrid, Selectively Targets GRP78.

Natural products discovered by using agnostic approaches, unlike rationally designed leads or those obtained through high-throughput screening, offer the ability to reveal new biological pathways and, hence, serve as an important vehicle to unveil new avenues in drug discovery. The ritterazine-cephalostatin family of natural products displays robust and potent antitumor activities, with sub-nanomolar growth inhibition against multiple cell lines and potent activity in xenograft models. Herein, we used comparative cellular and molecular biological methods to uncover the ritterazine-cephalostatin cytotoxic mode of action (MOA) in human tumor cells. Our findings indicated that, whereas ritterostatin GN 1N , a cephalostatin-ritterazine hybrid, binds to multiple HSP70s, its cellular trafficking confines activity to the endoplasmic reticulum (ER)-based HSP70 isoform, GRP78. This targeting results in activation of the unfolding protein response (UPR) and subsequent apoptotic cell death.