Computational approaches for simulating luminogenesis.

Lumens, liquid-filled cavities surrounded by polarized tissue cells, are elementary units involved in the morphogenesis of organs. Theoretical modeling and computations, which can integrate various factors involved in biophysics of morphogenesis of cell assembly and lumens, may play significant roles to elucidate the mechanisms in formation of such complex tissue with lumens. However, up to present, it has not been documented well what computational approaches or frameworks can be applied for this purpose and how we can choose the appropriate approach for each problem. In this review, we report some typical lumen morphologies and basic mechanisms for the development of lumens, focusing on three keywords - mechanics, hydraulics and geometry - while outlining pros and cons of the current main computational strategies. We also describe brief guidance of readouts, i.e., what we should measure in experiments to make the comparison with the model's assumptions and predictions.

Pre-Operative Four Dimensional Flow Sensitive Magnetic Resonance Imaging Assessment of Aortic Side Branches as a Method to Predict Risk of Type II Endoleak Resulting in Sac Enlargement After EVAR.

OBJECTIVE: To predict sac enlargement with type II endoleak (ELII) before endovascular aneurysm repair (EVAR) using four dimensional flow sensitive magnetic resonance imaging (4D flow MRI). METHODS: A single centre retrospective analysis of prospectively collected data was conducted. Patients with an abdominal aortic aneurysm (AAA) who underwent EVAR between 2013 and 2019 were included. Aortic branches occluded pre-EVAR, and patients with endoleaks other than ELII were excluded. The aortic branch diameter, peak flow velocity (PFVe), and amplitude of the dynamics of flow volume (AFV) were measured in each aortic branch pre-EVAR. Total flow volume per minute (TFV/min), defined as the sum of AFV/min, was calculated in each case. According to computed tomography findings one year post-EVAR, the aortic branches and patients were divided into patent vessel and occluded vessel groups and sac expanding and non-expanding groups. PFVe, AFV/min, and TFV/min were analysed via receiver operating characteristic curve analysis. RESULTS: The patent aortic branches pre-EVAR (69 inferior mesenteric arteries [IMAs]; 249 lumbar arteries [LAs]) of 100 patients were included. Patent IMAs (n = 14) and occluded IMAs (n = 55), patent LAs (n = 23) and occluded LAs (n = 226), and expanding (n = 9) and non-expanding (n = 91) groups were compared, respectively. No statistically significant difference was observed in branch diameters (IMA; patent, 2.5 ± 0.8 mm, occluded, 2.5 ± 0.8 mm, p < .78 and LA; patent, 1.5 ± 0.3 mm, occluded, 1.5 ± 0.4 mm, p < .35). PFVe (IMA; patent, 262.6 mm2/sec, occluded, 183.4 mm2/sec and LA; patent, 142.6 mm2/sec, occluded, 47.7 mm2/sec) and AFV/min (IMA; patent, 8.4 mL, occluded, 5.2 mL and LA; patent, 4.2 mL, occluded, 1.4 mL) were higher in the patent vessel group (p < .050). TFV/min was statistically significantly higher in the expanding group (24.1 mL/min) than in the non-expanding group (7.0 mL/min) (p < .010). CONCLUSION: Pre-EVAR haemodynamic analyses using 4D flow MRI were useful to detect aortic branches responsible for ELII and to predict AAA cases with sac enlargement. This analysis suggests a new strategy for pre-EVAR aortic branch embolisation.

Topological defects control collective dynamics in neural progenitor cell cultures.

Cultured stem cells have become a standard platform not only for regenerative medicine and developmental biology but also for biophysical studies. Yet, the characterization of cultured stem cells at the level of morphology and of the macroscopic patterns resulting from cell-to-cell interactions remains largely qualitative. Here we report on the collective dynamics of cultured murine neural progenitor cells (NPCs), which are multipotent stem cells that give rise to cells in the central nervous system. At low densities, NPCs moved randomly in an amoeba-like fashion. However, NPCs at high density elongated and aligned their shapes with one another, gliding at relatively high velocities. Although the direction of motion of individual cells reversed stochastically along the axes of alignment, the cells were capable of forming an aligned pattern up to length scales similar to that of the migratory stream observed in the adult brain. The two-dimensional order of alignment within the culture showed a liquid-crystalline pattern containing interspersed topological defects with winding numbers of +1/2 and -1/2 (half-integer due to the nematic feature that arises from the head-tail symmetry of cell-to-cell interaction). We identified rapid cell accumulation at +1/2 defects and the formation of three-dimensional mounds. Imaging at the single-cell level around the defects allowed us to quantify the velocity field and the evolving cell density; cells not only concentrate at +1/2 defects, but also escape from -1/2 defects. We propose a generic mechanism for the instability in cell density around the defects that arises from the interplay between the anisotropic friction and the active force field.

Active colloid with externally induced periodic bipolar motility and its cooperative motion.

Active matter physics has been developed with various types of self-propelled particles, including those with polar and bipolar motility and beyond. However, the bipolar motions experimentally realized so far have been either random along the axis or periodic at intrinsic frequencies. Here we report another kind of bipolar active particles, whose periodic bipolar self-propulsion is set externally at a controllable frequency. We used Quincke rollers-dielectric particles suspended in a conducting liquid driven by an electric field-under an AC electric field instead of the usually used DC field. Reciprocating motion of a single particle at the external frequency was observed experimentally and characterized theoretically as stable periodic motion. Experimentally, we observed not only the reciprocating motion but also non-trivial active Brownian particle (ABP)-like persistent motion in a long time scale. This resulted in a Lorentzian spectrum around zero frequency, which is not accounted for by a simple extension of the conventional model of Quincke rollers to the AC field. It was found that ABP-like motion can be reproduced by considering the top-bottom asymmetry in the experimental system. Moreover, we found a rotational diffusion coefficient much larger than the thermal one, as also reported in previous experiments, which may have resulted from roughness of the electrode surface. We also found self-organized formation of small clusters, such as doublets and triplets, and characterized cooperative motion of particles therein. The AC Quincke rollers reported here may serve as a model experimental system of bipolar active matter, which appears to deserve further investigations.

Potential role of transforming growth factor-beta 1/Smad signaling in secondary lymphedema after cancer surgery.

Secondary lymphedema often develops after cancer surgery, and over 250 million patients suffer from this complication. A major symptom of secondary lymphedema is swelling with fibrosis, which lowers the patient's quality of life, even if cancer does not recur. Nonetheless, the pathophysiology of secondary lymphedema remains unclear, with therapeutic approaches limited to physical or surgical therapy. There is no effective pharmacological therapy for secondary lymphedema. Notably, the lack of animal models that accurately mimic human secondary lymphedema has hindered pathophysiological investigations of the disease. Here, we developed a novel rat hindlimb model of secondary lymphedema and showed that our rat model mimics human secondary lymphedema from early to late stages in terms of cell proliferation, lymphatic fluid accumulation, and skin fibrosis. Using our animal model, we investigated the disease progression and found that transforming growth factor-beta 1 (TGFB1) was produced by macrophages in the acute phase and by fibroblasts in the chronic phase of the disease. TGFB1 promoted the transition of fibroblasts into myofibroblasts and accelerated collagen synthesis, resulting in fibrosis, which further indicates that myofibroblasts and TGFB1/Smad signaling play key roles in fibrotic diseases. Furthermore, the presence of myofibroblasts in skin samples from lymphedema patients after cancer surgery emphasizes the role of these cells in promoting fibrosis. Suppression of myofibroblast-dependent TGFB1 production may therefore represent an effective pharmacological treatment for inhibiting skin fibrosis in human secondary lymphedema after cancer surgery.

Optimal run-and-tumble-based transportation of a Janus particle with active steering.

Although making artificial micrometric swimmers has been made possible by using various propulsion mechanisms, guiding their motion in the presence of thermal fluctuations still remains a great challenge. Such a task is essential in biological systems, which present a number of intriguing solutions that are robust against noisy environmental conditions as well as variability in individual genetic makeup. Using synthetic Janus particles driven by an electric field, we present a feedback-based particle-guiding method quite analogous to the "run-and-tumbling" behavior of Escherichia coli but with a deterministic steering in the tumbling phase: the particle is set to the run state when its orientation vector aligns with the target, whereas the transition to the "steering" state is triggered when it exceeds a tolerance angle [Formula: see text] The active and deterministic reorientation of the particle is achieved by a characteristic rotational motion that can be switched on and off by modulating the ac frequency of the electric field, which is reported in this work. Relying on numerical simulations and analytical results, we show that this feedback algorithm can be optimized by tuning the tolerance angle [Formula: see text] The optimal resetting angle depends on signal to noise ratio in the steering state, and it is shown in the experiment. The proposed method is simple and robust for targeting, despite variability in self-propelling speeds and angular velocities of individual particles.

Flow dynamics of type II endoleaks can determine sac expansion after endovascular aneurysm repair using four-dimensional flow-sensitive magnetic resonance imaging analysis.

OBJECTIVE: The objective of this study was to investigate the hemodynamic parameters of type II endoleaks (T2ELs) to predict sac expansion using four-dimensional flow-sensitive magnetic resonance imaging (4D-flow MRI) analysis. METHODS: Patients who underwent endovascular aneurysm repair (EVAR) and were diagnosed with a T2EL were included in the study. Using 4D-flow MRI at 7 days, the peak flow velocity and amplitude of dynamics of blood flow per minute were measured in each T2EL vessel. The peak flow velocity was defined as the maximum of the absolute value of the blood flow velocity. The amplitude of dynamics of blood flow in the tributary arteries was defined as the sum of the absolute values of the inflow and outflow volume in each vessel. The amplitude of dynamics of blood flow in the tributary arteries per sac was calculated in each sac. The aneurysm sac diameter was measured by computed tomography (CT) at 1 year. The patients were divided into two groups according to the presence or absence of sac expansion. RESULTS: Of 155 patients who underwent EVAR, both CT angiography and 4D-flow MRI were performed in 107 patients at 7 days after EVAR. Among them, 39 (36.4%) were found to have a T2EL, of whom 28 were re-evaluated with CT angiography and 4D-flow at 1 year; 7 patients had expanding sacs (expanding group), whereas 21 had nonexpanding sacs (not-expanding group). At 7 days, 28 patients had 80 T2EL vessels detected by 4D-flow MRI, of which 39 vessels (48.8%) had stopped flowing at 1 year (transient vessels); 41 vessels (51.3%) had sustained flow (persistent vessels). The persistent vessels had significantly larger peak flow velocity and amplitude of dynamics of blood flow. The comprehensive analysis of T2EL vessels per sac identified that the amplitude of dynamics of blood flow in the tributary arteries per sac was significantly higher in the expanding group than in the not-expanding group. A receiver operating characteristic curve analysis revealed that the sensitivity and specificity of sac enlargement at a cutoff value of 3750 mm3/min were 85.7% and 76.2%, respectively. CONCLUSIONS: The fate of aneurysm sacs with T2ELs after EVAR has remained difficult to predict. A comprehensive analysis of concurrent multiple T2EL vessels using 4D-flow MRI analysis may enable prediction of the sac expansion after EVAR.

Sampling strategy and climatic implication of tree-ring cellulose oxygen isotopes of Hippophae tibetana and Abies georgei on the southeastern Tibetan Plateau.

The tree-ring cellulose oxygen isotopes (δ18O) for four trees of Hippophae tibetana and four trees of Abies georgei growing in different locations around the terminal moraine in Xincuo from 1951 to 2010 were measured to explore its potential for reconstructing climatic variations in the southeastern Tibetan Plateau. The mean and standard deviation of tree-ring δ18O at different heights do not have significant differences, and there are no significant differences in the mean and standard deviation of tree-ring δ18O between trees near the brook and trees at the top of moraine, indicating that we can collect samples for tree-ring δ18O analysis regardless of sampling heights and that the micro-environment does not affect tree-ring δ18O significantly. The mean inter-series correlations of cellulose δ18O for A. georgei/H. tibetana are 0.84/0.93, and the correlation between δ18O for A. georgei and H. tibetana is 0.92. The good coherence between inter-tree and inter-species cellulose δ18O demonstrates the possibility of using different species to develop a long chronology. Correlation analysis between tree-ring δ18O and climate parameters revealed that δ18O for A. georgei/H. tibetana had negative correlations (r = -0.62/r = -0.69) with relative humidity in July-August, and spatial correlation revealed that δ18O for A. georgei/H. tibetana reflected the regional Standardized Precipitation Evapotranspiration Index (29°-32° N, 88°-98° E). In addition, tree-ring δ18O in Xincuo has a significant correlation with tree-ring δ18O in Bhutan. The results indicate that cellulose δ18O for A. georgei and H. tibetana in Xincuo is a good proxy for the regional hydroclimate.

Chirality-induced helical self-propulsion of cholesteric liquid crystal droplets.

We report the first experimental realization of a chiral artificial microswimmer exhibiting helical motion without any external fields. We discovered that a cholesteric liquid crystal (CLC) droplet with a helical director field swims in a helical path driven by the Marangoni flow in an aqueous surfactant solution. We also showed that the handedness of the helical path is reversed when that of the CLC droplet is reversed by replacing the chiral dopant with the enantiomer. In contrast, nematic liquid crystal (NLC) droplets exhibited ballistic motions. These results suggest that the helical motion of the CLC droplets is driven by chiral couplings between the Marangoni flow and rotational motion via the helical director field of CLC droplets.

Hemodynamic Analysis of Endoleaks After Endovascular Abdominal Aortic Aneurysm Repair by Using 4-Dimensional Flow-Sensitive Magnetic Resonance Imaging.

BACKGROUND: An endoleak is a common complication of endovascular abdominal aortic aneurysm repair (EVAR), and it can be associated with aneurysmal growth. This pilot study used 4-dimensional flow-sensitive magnetic resonance imaging (4D-flow) to assess the hemodynamics of different types of endoleaks (I-IV). METHODS AND RESULTS: Magnetic resonance angiography, 4D-flow, and computed tomography angiography (CTA) were performed in 31 patients after nitinol-based stent-graft deployment. With 4D-flow, the 3D streamlines of endoleaks appear as integrated traces along the instantaneous velocity vector field that are color-coded according to the local velocity magnitude of the leak. The 4D-flow analysis identified endoleaks in 18 patients (58.1%), whereas CTA identified endoleaks in 13 patients (41.9%). The 4D-flow analysis created a characteristic image of each type of endoleak. Among patients with endoleaks, 4D-flow identified concomitant multiple endoleaks in 7 (39%) patients, and it further differentiated type II endoleaks from type IIa endoleaks (to-and-fro biphasic flow pattern from a branch vessel) and from type IIb endoleaks (monophasic flow pattern with a connection between the inflow and outflow branches). CONCLUSIONS: The 4D-flow analysis was more sensitive than CTA for detecting an endoleak, and it could subclassify type II endoleaks. In addition, 4D-flow differentiated between concomitant endoleak types in a single patient. (Circ J 2016; 80: 1715-1725).

Imaging Mass Spectrometry Reveals a Unique Distribution of Triglycerides in the Abdominal Aortic Aneurysmal Wall.

The pathophysiology underlying abdominal aortic aneurysms (AAAs) remains unknown. In this study, we applied imaging mass spectrometry (IMS) to analyze the pathophysiology of the aneurysmal wall. Comparisons were performed between the tissue samples from the neck and the sac of the AAA, at a single time point, in 30 patients who underwent elective surgery of their AAAs. The localization of each lipid molecule in the aortic wall was assessed by IMS. Histopathological examination and IMS revealed a characteristic distribution of triglycerides (TGs) specifically in the aneurismal adventitia of the sac. This characteristic TG distribution was derived from an ectopic appearance of adipocytes in the adventitia. Furthermore, ectopic adipocyte accumulation in the aortic wall leads to the loss of the collagen fiber network subsequent to the wall rupture. The underlying mechanism of adipocyte accumulation involves the presence of adipose-derived stem cells (ADSCs) in the aneurismal adventitia and the expression of peroxisome proliferator-activated receptor gamma 2, a master regulator of adipocyte differentiation by some ADSCs. This study reveals new, previously overlooked aspects of AAA pathology.

Quantitative assessment of the free jejunal graft perfusion.

BACKGROUND: Reconstruction with free jejunal graft (FJG) is often performed for patients with hypopharyngeal or cervical esophageal cancer. During reconstruction with an FJG after pharyngoesophagectomy, it is critical to intraoperatively detect venous anastomotic failure and subsequent venous malperfusion to avoid postoperative FJG necrosis. This study introduces a novel method for assessing blood perfusion in FJGs by using indocyanine green (ICG) fluorescence angiography. METHODS: We used ICG fluorescence angiography to quantitatively assess FJG blood perfusion in archived fluorescence video files from 26 patients who had undergone FJG transfer. A software program "ROIs", was used to create a time-fluorescence intensity curve. We retrospectively measured the maximum fluorescence intensity at the terminal ileum and the duration (T1/2max) between when the intensity began rising and when it reached half of the maximum. RESULTS: Among the 26 patients, 5 patients suffered venous anastomotic failure. In three of these cases, anastomosis was corrected intraoperatively; the other two patients underwent a second FJG transfer. Retrospective assessment showed that the mean T1/2max at the FJG serosae was significantly longer in these five patients than that in FJGs with good blood perfusion. Our analysis revealed that a T1/2max >9.6 s may be a good indicator of FJG venous malperfusion. CONCLUSIONS: Quantitative analysis of ICG fluorescence angiography proved useful for detecting venous anastomotic failure of FJG, and may help to reduce vascular problems in FJG reconstruction.

Early outcomes of iliac branch grafts in the endovascular repair of abdominal aortic aneurysms with concomitant bilateral common iliac artery aneurysms at a Japanese institution.

PURPOSE: Endovascular aneurysm repair (EVAR) is used to treat abdominal aortic aneurysms (AAAs) with bilateral common iliac artery aneurysms (CIAAs), and an interruption of the bilateral internal iliac arteries (IIAs) is often needed, which may cause postoperative ischemic complications. An iliac branch device (IBD) has thus been introduced as an endovascular technique to preserve the IIA flow. This study aimed to evaluate the technical feasibility and short-term results of using an IBD when treating AAA with bilateral CIAAs in a Japanese institution, where IBD use has still not been approved by the government. METHODS: EVAR was performed using an IBD in six patients at high risk for open repair of an AAA with bilateral CIAAs. RESULTS: Advanta V12 stent grafts were successfully placed in the IIA, bridging between the IIA and the IBD side branch from the contralateral iliac artery. Subsequently, EVAR was performed as usual. The technical success rate was 100 %. At the most recent follow-up (mean follow-up period, 14.2 months), all IBDs were patent. No patients complained of buttock claudication or ischemic colitis. CONCLUSIONS: The implantation of an IBD during EVAR is technically feasible in Japanese AAA patients with bilateral CIAAs, and may be a viable method to avoid pelvic ischemic complications, such as intractable buttock claudication.

A simple force-motion relation for migrating cells revealed by multipole analysis of traction stress.

For biophysical understanding of cell motility, the relationship between mechanical force and cell migration must be uncovered, but it remains elusive. Since cells migrate at small scale in dissipative circumstances, the inertia force is negligible and all forces should cancel out. This implies that one must quantify the spatial pattern of the force instead of just the summation to elucidate the force-motion relation. Here, we introduced multipole analysis to quantify the traction stress dynamics of migrating cells. We measured the traction stress of Dictyostelium discoideum cells and investigated the lowest two moments, the force dipole and quadrupole moments, which reflect rotational and front-rear asymmetries of the stress field. We derived a simple force-motion relation in which cells migrate along the force dipole axis with a direction determined by the force quadrupole. Furthermore, as a complementary approach, we also investigated fine structures in the stress field that show front-rear asymmetric kinetics consistent with the multipole analysis. The tight force-motion relation enables us to predict cell migration only from the traction stress patterns.

Intraoperative lymph mapping with preoperative vein mapping to prevent postoperative lymphorrhea following paramalleolar bypass surgery in patients with critical limb ischemia.

PURPOSE: Paramalleolar bypass surgery requires a long incision to harvest the great saphenous vein (GSV), which is often associated with intractable postoperative lymphorrhea. To prevent this complication, we developed a novel method of intraoperative lymph imaging and preoperative vein mapping for vein harvesting. METHODS: Thirteen consecutive patients with critical limb ischemia (CLI) underwent both preoperative vein mapping and intraoperative lymph mapping (Group A). Duplex vein mapping was performed to mark the GSV. Lymph mapping was performed with indocyanine green fluorescence lymphography. Paramalleolar bypasses were performed using reversed GSV grafts, with careful ligation of the subcutaneous lymph collector vessels above the GSV. The development of intractable postoperative lymphorrhea and the length of the postoperative hospital stay were compared with those in the previous ten consecutive CLI patients without lymph mapping who underwent paramalleolar bypass (Group B). RESULTS: The occurrence of intractable wound lymphorrhea by the 30th postoperative day was 3/10 (30 %) in Group B, while it was 0/13 (0 %) in Group A (p < 0.05). The length of the postoperative hospital stay was 31.7 ± 8.8 and 57.5 ± 39.5 days (Group A and Group B, respectively, p < 0.05). CONCLUSIONS: Intraoperative lymph mapping and preoperative vein mapping are technically feasible and can positively contribute to the prevention of postoperative lymphorrhea after GSV harvesting.

Development of an Undifferentiated Pleomorphic Sarcoma After Aortic Aneurysm Graft Replacement: A Case Report and Literature Review.

Aortic sarcomas are extremely rare. Sarcomas associated with aortic graft replacement are even rarer; only 17 cases have been examined through immunohistochemical staining to date, most of which were either angiosarcomas or intimal sarcomas. Here, we report the case of an 88-year-old man with an undifferentiated pleomorphic sarcoma (UPS) that developed after aortic graft replacement and was diagnosed through postmortem autopsy. To the best of our knowledge, this is the first case of graft-associated sarcoma diagnosed as an undifferentiated pleomorphic type following detailed immunohistochemical staining with sufficient antibodies and fluorescencein situ hybridization (FISH).

Reversible Host-Guest Crosslinks in Supramolecular Hydrogels for On-Demand Mechanical Stimulation of Human Mesenchymal Stem Cells.

Stem cells are regulated not only by biochemical signals but also by biophysical properties of extracellular matrix (ECM). The ECM is constantly monitored and remodeled because the fate of stem cells can be misdirected when the mechanical interaction between cells and ECM is imbalanced. A well-defined ECM model for bone marrow-derived human mesenchymal stem cells (hMSCs) based on supramolecular hydrogels containing reversible host-guest crosslinks is fabricated. The stiffness (Young's modulus E) of the hydrogels can be switched reversibly by altering the concentration of non-cytotoxic, free guest molecules dissolved in the culture medium. Fine-adjustment of substrate stiffness enables the authors to determine the critical stiffness level E* at which hMSCs turn the mechano-sensory machinery on or off. Next, the substrate stiffness across E* is switched and the dynamic adaptation characteristics such as morphology, traction force, and YAP/TAZ signaling of hMSCs are monitored. These data demonstrate the instantaneous switching of traction force, which is followed by YAP/TAZ signaling and morphological adaptation. Periodical switching of the substrate stiffness across E* proves that frequent applications of mechanical stimuli drastically suppress hMSC proliferation. Mechanical stimulation across E* level using dynamic hydrogels is a promising strategy for the on-demand control of hMSC transcription and proliferation.

Cooperative and stochastic calcium releases from multiple calcium puff sites generate calcium microdomains in intact Hela cells.

Ca(2+) microdomains or locally restricted Ca(2+) increases in the cell have recently been reported to regulate many essential physiological events. Ca(2+) increases through the inositol 1,4,5-trisphosphate (IP(3)) receptor (IP(3)R)/Ca(2+) release channels contribute to the formation of a class of such Ca(2+) microdomains, which were often observed and referred to as Ca(2+) puffs in their isolated states. In this report, we visualized IP(3)-evoked Ca(2+) microdomains in histamine-stimulated intact HeLa cells using a total internal reflection fluorescence microscope, and quantitatively characterized the spatial profile by fitting recorded images to a two-dimensional Gaussian distribution. Ca(2+) concentration profiles were marginally spatially anisotropic, with the size increasing linearly even after the amplitude began to decline. We found the event centroid drifted with an apparent diffusion coefficient of 4.20 ± 0.50 µm(2)/s, which is significantly larger than those estimated for IP(3)Rs. The sites of maximal Ca(2+) increase, rather than initiation or termination sites, were detected repeatedly at the same location. These results indicate that Ca(2+) microdomains in intact HeLa cell are generated from spatially distributed multiple IP(3)R clusters or Ca(2+) puff sites, rather than a single IP(3)R cluster reported in cells loaded with Ca(2+) buffers.

Climate as a contributing factor in the demise of Angkor, Cambodia.

The "hydraulic city" of Angkor, the capitol of the Khmer Empire in Cambodia, experienced decades-long drought interspersed with intense monsoons in the fourteenth and fifteenth centuries that, in combination with other factors, contributed to its eventual demise. The climatic evidence comes from a seven-and-a-half century robust hydroclimate reconstruction from tropical southern Vietnamese tree rings. The Angkor droughts were of a duration and severity that would have impacted the sprawling city's water supply and agricultural productivity, while high-magnitude monsoon years damaged its water control infrastructure. Hydroclimate variability for this region is strongly and inversely correlated with tropical Pacific sea surface temperature, indicating that a warm Pacific and El Niño events induce drought at interannual and interdecadal time scales, and that low-frequency variations of tropical Pacific climate can exert significant influence over Southeast Asian climate and society.