Numerical study of the upwelling and downwelling effects of artificial reefs along tidal cycles in the Pearl River Estuary.

Artificial reefs (ARs) are a preferred option for managers due to their distinctive hydrodynamic properties, which support a highly productive local ecosystem. However, the hydrodynamics characteristics of ARs in natural marine environments have not been conducted. Being the first to explore the spatiotemporal characteristic of flow fields around ARs along tidal cycles in marine environments, this study redefined the upwelling and downwelling of ARs, based on natural vertical velocities, and separated the upwelling into co-direction upwelling and re-direction upwelling, and the downwelling into co-direction downwelling and re-direction downwelling. This study simulated the flow field in the Wanshan ARs area of the Pearl River Estuary along the tidal cycles using the MIKE3-FM. Numerical simulations revealed that (1) co-direction upwelling and co-direction downwelling were the dominant components of the vertical flow field effects of ARs; (2) the areas sum of upwelling and downwelling were largest in the medium water column, with about 1.6 and 1.03 times as large as the bottom and surface water column, respectively, while the fluxes sum of the upwelling and downwelling were largest in bottom water column, with approximately 1.3 and 2.2 times larger than those in the middle and surface water columns; (3) the area and volume of the upwelling and downwelling gradually decreased along neap-spring tide, exhibited significantly negative correlations with current speeds; while the upwelling flux and downwelling flux gradually increased along neap-spring tide; exhibited a significantly positive correlation with current speed; (4) the effects of tide to upwelling and downwelling of AR are forced by the northward velocity of current speed, the net flux of upwelling and downwelling showed a significant positive correlation with the northward velocity of current speed (r = 0.94). These results could provide a reference for assessing the flow field effect of ARs and a guide for the configuration and management of ARs.

Anomalous Structural Transformation of Cu(I) Clusters into Multifunctional CuAg Nanoclusters.

We report an anomalous structural transformation of a Cu(I) cluster into two different types of copper-silver (CuAg) alloy nanoclusters. Different from previous reports, we demonstrate that under specifically designed reaction conditions, the Ag-doping could induce a substantial growth of the starting Cu15 and a Ag13Cu20 nanocluster was obtained via the unexpected insertion of an Ag13 kernel inside the Cu(I)-S shell. Ag13Cu20 demonstrates high activity to initiate the photopolymerization of previously hard-to-print inorganic polymers in 3D laser microprinting. Interestingly, a slight modification of the reaction condition leads to the formation of another Ag18-xCuxS (8≤x) nanocluster templated by a central S2- anion, which possesses a unique electronic structure compared to conventional template-free CuAg nanoclusters. Overall, this work unveils the intriguing doping chemistry of Cu clusters, as well as their capability to create different types of alloy nanoclusters with previously unobtainable structures and multifunctionality.

Unveiling unique alternative splicing responses to low temperature in Zoysia japonica through ZjRTD1.0, a high-quality reference transcript dataset.

Inadequate reference databases in RNA-seq analysis can hinder data utilization and interpretation. In this study, we have successfully constructed a high-quality reference transcript dataset, ZjRTD1.0, for Zoysia japonica, a widely-used turfgrass with exceptional tolerance to various abiotic stress, including low temperatures and salinity. This dataset comprises 113,089 transcripts from 57,143 genes. BUSCO analysis demonstrates exceptional completeness (92.4%) in ZjRTD1.0, with reduced proportions of fragmented (3.3%) and missing (4.3%) orthologs compared to prior datasets. ZjRTD1.0 enables more precise analyses, including transcript quantification and alternative splicing assessments using public datasets, which identified a substantial number of differentially expressed transcripts (DETs) and differential alternative splicing (DAS) events, leading to several novel findings on Z. japonica's responses to abiotic stresses. First, spliceosome gene expression influenced alternative splicing significantly under abiotic stress, with a greater impact observed during low-temperature stress. Then, a significant positive correlation was found between the number of differentially expressed genes (DEGs) encoding protein kinases and the frequency of DAS events, suggesting the role of protein phosphorylation in regulating alternative splicing. Additionally, our results suggest possible involvement of serine/arginine-rich (SR) proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs) in generating inclusion/exclusion isoforms under low-temperature stress. Furthermore, our investigation revealed a significantly enhanced overlap between DEGs and differentially alternatively spliced genes (DASGs) in response to low-temperature stress, suggesting a unique co-regulatory mechanism governing transcription and splicing in the context of low-temperature response. In conclusion, we have proven that ZjRTD1.0 will serve as a reliable and useful resource for future transcriptomic analyses in Z. japonica.

Drinking brick tea containing high fluoride increases the prevalence of osteoarthritis in Tibetan, China.

The prevalence of osteoarthritis (OA) in Tibetans is higher than that in Han, while Tibetans have a habit of drinking brick tea with high fluoride. A cross-sectional study was conducted to explore the association between fluoride exposure in drinking brick tea and OA. All subjects were divided into four groups by the quartiles (Q) of tea fluoride (TF) and urine fluoride (UF). ROC was plotted and OR were obtained using logistic regression model. The prevalence of OA in the Q3 and Q4 group of TF were 2.2 and 2.7 times higher than in the Q1 group, and the prevalence of OA in the Q2, Q3 and Q4 group of UF were 3.2, 3.5, and 4.1 times higher than in the Q1 group. ROC analysis showed the cutoff values were 4.523 mg/day (TF) and 1.666 mg/L (UF). In conclusion, excessive fluoride in drinking brick tea could be a risk factor for developing OA.

Mechanical Performance of Copper-Nanocluster-Polymer Nanolattices.

A type of copper-nanocluster-polymer composites is reported and showcased that their 3D nanolattices exhibit a superior combination of high strength, toughness, deformability, resilience, and damage-tolerance. Notably, the strength and toughness of ultralight copper-nanocluster-polymer nanolattices in some cases surpass current best performers, including alumina, nickel, and other ceramic or metallic lattices at low densities. Additionally, copper-nanocluster-polymer nanolattices are super-resilient, crack-resistant, and one-step printed under ambient condition which can be easily integrated into sophisticated microsystems as highly effective internal protectors. The findings suggest that, unlike traditional nanocomposites, the laser-induced interface and the high fraction of ultrasmall Cu15 nanoclusters as crosslinking junctions contribute to the marked nonlinear elasticity of copper-nanocluster-polymer network, which synergizes with the lattice-topology effect and culminates in the exceptional mechanical performance.

Enabling Polymer Single Crystals to Be High-Performance Dielectric.

Semicrystalline polymer dielectrics (SPDs) are highly sought-after state-of-the-art dielectric materials. As the disorder in SPDs degrades their electrical properties, homogeneously ordered SPDs are desired. However, complex crystallization behaviors of polymers make such homogeneity elusive. Polymer lamellar single crystals (PLSCs), the most regularly-ordered form of SPDs possible under mild crystallizing conditions, are ideal platforms for understanding and developing high-performance dielectric materials. Here, a typical and widely used SPD, polyethylene (PE) is selected as the model material. We successfully obtained, large, uniform, and high-quality PE PLSCs and devised a non-destructive strategy to construct PE PLSC-based vertical capacitors. These nanometer-thick capacitors exhibit exceptional dielectric properties, with a high breakdown strength of 6.95 MV/cm and a low dielectric constant of 2.14±0.07, that outperform the properties of any existing neat PE. This work provides novel insights into exploring the performance possibility of ordered SPDs and reveals the PLSCs as potential high-performance dielectric materials.

Above 100% Efficiency Photocharge Generation in Monolayer Semiconductors by Singlet Fission Sensitization.

Sensitizing inorganic semiconductors using singlet fission (SF) materials, which produce two excitons from one absorbed photon, can potentially boost their light-to-electricity conversion efficiency. The SF sensitization is particularly exciting for two-dimensional (2D) layered semiconductors with atomically flat surface and high carrier mobility but limited light absorption. However, efficiently harnessing triplet excitons from SF by charge transfer at organic/inorganic interface has been challenging, and the intricate interplay among competing processes remains unresolved. Here, we investigate SF sensitization in high-quality organic/2D bilayer heterostructures featuring TIPS-Pc single crystals. Through transient magneto-optical spectroscopy, we demonstrate that despite an ultrafast SF process in sub-100 fs, a significant fraction of singlet excitons in TIPS-Pc dissociate at the interface before fission, while triplet excitons from SF undergo diffusion-limited charge transfer at the interface in ∼10 ps to ns. Remarkably, the photocharge generation efficiency reaches 126% in heterostructures with optimal thickness, resulting from the competitive interplay between singlet exciton fission, dissociation, and triplet exciton transport. This presents a promising strategy for advancing SF-enhanced 2D optoelectronics beyond the conventional limits.

Bcl-3 regulates T cell function through energy metabolism.

BACKGROUND: Bcl-3 is a member of the IκB protein family and an essential modulator of NF-κB activity. It is well established that Bcl-3 is critical for the normal development, survival and differentiation of adaptive immune cells, especially T cells. However, the regulation of immune cell function by Bcl-3 through metabolic pathways has rarely been studied. RESULTS: In this study, we explored the role of Bcl-3 in the metabolism and function of T cells via the mTOR pathway. We verified that the proliferation of Bcl-3-deficient Jurkat T cells was inhibited, but their activation was promoted, and Bcl-3 depletion regulated cellular energy metabolism by reducing intracellular ATP and ROS production levels and mitochondrial membrane potential. Bcl-3 also regulates cellular energy metabolism in naive CD4+ T cells. In addition, the knockout of Bcl-3 altered the expression of mTOR, Akt, and Raptor, which are metabolism-related genes, in Jurkat cells. CONCLUSIONS: This finding indicates that Bcl-3 may mediate the energy metabolism of T cells through the mTOR pathway, thereby affecting their function. Overall, we provide novel insights into the regulatory role of Bcl-3 in T-cell energy metabolism for the prevention and treatment of immune diseases.

Holocene climate change in southern Oman deciphered by speleothem records and climate model simulations.

Qunf Cave oxygen isotope (δ18Oc) record from southern Oman is one of the most significant of few Holocene Indian summer monsoon cave records. However, the interpretation of the Qunf δ18Oc remains in dispute. Here we provide a multi-proxy record from Qunf Cave and climate model simulations to reconstruct the Holocene local and regional hydroclimate changes. The results indicate that besides the Indian summer monsoon, the North African summer monsoon also contributes water vapor to southern Oman during the early to middle Holocene. In principle, Qunf δ18Oc values reflect integrated oxygen-isotope fractionations over a broad moisture transport swath from moisture sources to the cave site, rather than local precipitation amount alone, and thus the Qunf δ18Oc record characterizes primary changes in the Afro-Asian monsoon regime across the Holocene. In contrast, local climate proxies appear to suggest an overall slightly increased or unchanged wetness over the Holocene at the cave site.

Multi-Functionalization of Single crystals Mediated by Gel-Incorporation: A Bioinspired Strategy.

Biominerals are inherently organic-inorganic crystal composites. Drawing inspiration from this biomineral structure, functionalized single crystals can be synthesized using the gel-grown method, resulting in the incorporation of gel-networks into the host crystals. By incorporating gel-networks, diverse guest materials, such as nanoparticles and dye molecules, can be uniformly and isotropically distributed within the crystals, thereby imparting non-intrinsic optical or magnetic properties to the host crystals. Additionally, gel-incorporation enhances the toughness and stability of the crystals as the incorporated gel-fibers and accompanying guest materials act as bridges to prevent crack propagation. Furthermore, gel-incorporation enables protein crystals to exhibit self-healing properties, which can be attributed to the dynamic bonding interaction between gel-networks and crystals. Notably, recent research has demonstrated that the incorporation of zwitterionic gel-networks enhances the charge effects on crystal morphology evolution as the charged groups become bound to the developing crystal surfaces, and their detachment is impeded by the interconnected gel-networks. Therefore, preparing single crystals with gel-incorporation is a remarkable strategy for synthesizing functionalized crystal materials.

Effects of artificial reef and fishing moratorium on trophic structure of biological community in the Pearl River Estuary marine ranch based on stable isotopes.

Deployment of artificial reefs (ARs) has become popular technique to create new hard-bottom habitats, increase biodiversity and richness for fisheries. We compared the faunal community structure and food web structure associated with before and after fishing moratorium between ARs and non-ARs in Wanshan Island, Pearl River Estuary using stable isotope techniques. Community composition showed higher differences between ARs and non-ARs. The range of δ13C and δ15N of different functional groups can distinguish the pelagic and benthic trophic pathways of the food web in reef-or-not area before and after fishing moratorium. The isotopic niches of entire faunal, as well as individual functional groups, overlapped less between ARs and non-ARs in Wanshan Island, which makes the isotopic functional indices non-equivalent. The total convex hull area (TA) of ARs was larger than that of non-ARs, indicating that nutrient pathways of ARs were more diverse. Overall, however, these results suggest that trophic structure was convergence between ARs and non-ARs, and differences before and after fishing moratorium, possibly due to seasonal differences. Finally, it was shown that the construction of ARs had a weak effect on the restoration of fishery resources in this area, which might be related to lack of further management, or even similar community composition to non-ARs areas.

Enhancing the Uniformity of Organic Field-Effect Transistors by a Single-Crystalline Layer-Controlled Active Channel.

Despite remarkable improvement in the mobility of the organic field-effect transistors (OFETs) being achieved in past decades, the uniformity in electrical performance remains ambiguous, impeding their implantation in organic integrated circuits. The coefficient of variance (CV) in mobility of reported OFETs is typically larger than 8%, which is not adequate for building medium-to-large scale integrated circuits. In this work, it is shown that utilizing single-domain molecular monolayer crystals as the active channel can largely enhance the uniformity of OFETs. Benefiting from the sole molecular layer with long-range ordering, the OFETs exhibit uniformities in both channel transport and charge injection, thereby giving rise to a high average mobility of 11.64 cm2 V-1 s-1 and CV of only 2.57%. Statistical transmission length method evaluation is conducted, covering channel length from 3 to 21 µm, channel width from 90 to 170 µm, and a total OFET number of 370. The low contact resistance of 79.00 ± 7.00 Ω cm and high intrinsic mobility of 12.36 ± 0.45 cm2 V-1 s-1 are acquired with very high accuracy and reliability. As such, this work provides a practical way to enhance the uniformity of OFETs by a single-crystalline layer-controlled active channel toward their applications in integrated circuits.

Long-Range Ordered Organic Bulk-Heterojunction: C60 and O-IDTBR Single Crystals Penetrated by Crystalline P3HT Fibrous Networks.

The long-range ordering of bulk-heterojunctions (BHJs) significantly facilitates exciton diffusion and dissociation as well as charge transport. A feasible bio-inspired strategy to realize such a heterostructure is crystallization in gel media where the growing host crystals incorporate the surrounding guest materials of gel networks. Until now, the host-guest pairs forming ordered BHJs are still very limited and, more importantly, the used gel-network guests are structurally amorphous, spurring investigation toward crystalline gel-networks. Here, single crystals of fullerene and non-fullerene acceptors (NFAs) in poly(3-hexylthiophene) (P3HT) organogel are prepared, forming C60 :P3HT and (5Z,5″Z)-5,5″-((7,7″-(4,4,9,9-tetraoctyl-4,9-dihydro-s-indaceno[1,2-b:5,6-b″]dithiophene-2,7-diyl)bis(benzo[c][1,2,5]thiadiazole-7,4-diyl))bis(methanylylidene))bis(3-ethyl-2-thioxothiazolidin-4-one) (O-IDTBR):P3HT BHJs. The crystalline P3HT network penetrates the crystal matrix without significantly disturbing the single crystallinity, resulting in long-range ordered BHJs. This bi-continuous structure, together with an improved overall ordering, contributes to enhanced charge/energy transfer. As a result, photodetectors based on these ordered BHJs exhibit ameliorated responsivity, detectivity, bandwidth, and stability as compared to the conventional BHJs with short-range ordering. Therefore, this work further extends the scope of long-range ordered BHJs toward crystalline polymer donors and NFAs, providing a generally applicable strategy for the design of organic optoelectronic devices with superior performance.

Sex and Age Differences in Association between Physical Activity and Metabolic Syndrome: Results from NHANES 2003-2006.

OBJECTIVE: To examine whether and how sex and age modify the association between accelerometer-based physical activity (PA) and metabolic syndrome (MetS) among American (US) adults. METHOD: Adults aged ≥20 years old who participated in the mobile center examination during 2003-2006 in the National Health and Nutrition Examination Survey were included for analysis. The total minutes per day of moderate-to-vigorous PA (MVPA) was estimated using ActiGraph. Multivariable logistic regression was used to estimate the odds ratio (OR) of having MetS at an increasing MVPA time. The modification effects of gender and age on the association between MetS and MVPA time were examined by testing for two-way and three-way interaction terms of MVPA time, sex, and age in the model after adjusting for relevant covariates. RESULTS: The prevalence of MetS generally decreased with the MVPA time and was lower in females than in males, although the sex difference varied across age groups. After adjusting for demographic and lifestyle covariates, there was a significant sex difference in how an increased MVPA time lowered the odds of MetS. This interactive effect also varied with age. MVPA benefitted young and middle-age populations up until about 65 years old for both sexes, and the protective effect weakened with age. Although the effect of MVPA was stronger for males than females at young ages, the rate at which it attenuated was quicker in males. The OR of MetS between males and females per unit change of MVPA time was 0.73 (95% CI: [0.57, 0.93]) at age = 25 years, compared to OR = 1.00 (95% CI: [0.88, 1.16]) at age = 60 years. Before the age of 50, the gender difference in the protective effect on MetS was larger at low MVPA levels and became smaller at higher MVPA levels. The male advantage was quite stable with an increasing MVPA time for ages 50-60, and no longer significant at older ages. CONCLUSIONS: Young and middle-age populations benefitted from MVPA, lowering the risk of MetS for both sexes. A longer MVPA time was associated with a greater decrease in the risk of MetS in young men than in women, but the sex difference reduced with age and was no longer apparent in older populations.

Zwitterionic Separator Featured with Superdesolvating Properties for High Performance Lithium-Sulfur Batteries.

Lithium-sulfur chemistry has greatly expanded the boundaries of lithium batteries, but the persistent parasitic reaction of soluble sulfur intermediates with lithium anode remains a primary challenge. Understanding and regulating the solvation structures of lithium ions (Li+) and polysulfides (LiPSs) are critical to addressing the above issues. Herein, inspired by the natural superhydrophilic resistance to contamination, we developed a zwitterionic nanoparticles (ZWP) separator capable of modulating the solvated of Li+ and LiPSs. The dense solvated layer induced by ZWP effectively prevents the movement of LiPSs without compromising Li+ transport. Moreover, the high electrolyte affinity of the ZWP effectively results in minimizing the deposition of LiPSs on the separator. Furthermore, the structure of the solvated Li+ and LiPSs is also unveiled by molecular simulation and nuclear magnetic resonance (NMR). In addition, in situ UV setup proved the ZWP separator can effectively suppress the shuttle of LiPSs. The restricted space formed by the tightly packed ZWP stabilizes the lithium deposition and regulates dendrite growth. Consequently, the performance of lithium-sulfur batteries is significantly improved and good cycle stability is maintained even at high sulfur loadings (5 mg cm-2). This contribution provides a new insight into the rational design of lithium-sulfur battery separators.

Morphological Evolution of Calcite Grown in Zwitterionic Hydrogels: Charge Effects Enhanced by Gel-Incorporation.

The incorporation of charged biomacromolecules is widely found in biomineralization. To investigate the significance of this biological strategy for mineralization control, gelatin-incorporated calcite crystals grown from gelatin hydrogels with different charge concentrations along the gel networks are examined. It is found that the bound charged groups on gelatin networks (amino cations, gelatin-NH3 + and carboxylic anions, gelatin-COO- ) play crucial roles in controlling the single-crystallinity and the crystal morphology. And the charge effects are greatly enhanced by the gel-incorporation because the incorporated gel networks force the bound charged groups on them to attach to crystallization fronts. In contrast, ammonium ions (NH4 + ) and acetate ions (Ac- ) dissolve in the crystallization media do not exhibit the similar charge effects because the balance of attachment/detachment make them more difficult to be incorporated. Employing the revealed charge effects, the calcite crystal composites with different morphologies can be flexibly prepared.

Construction and influencing factors of an early warning system for marine ranching ecological security: Experience from China's coastal areas.

Marine ranching has been widely considered as a new mode of marine fishery production. Marine ranching ecological security (MRES) is the basis and premise to ensure the sustainable utilization of marine ranching functions. In this study, an MRES early warning system was constructed based on comprehensive marine ranching ecological security index (CMRESI) and system dynamic model to reveal the main factors affecting the development of marine ranching and explore the changes in MRES under different future development scenarios in China's coastal areas from 2011 to 2035. The results showed that (1) the mean CMRESI of China was only 0.3265 and spatial heterogeneity was significant, showing a general security state; (2) coupling and coordination degree of MRES subsystems was high in Jiangsu, Fujian, Shandong, and Guangdong, and resources was a major constraint on the coordinated development of MRES in the study area (63.6%); (3) Under the ecological priority development scenario, the CMRESI will be the highest in 2035; however, 27% of MRES (in Jiangsu, Fujian, and Hainan) will continue to issue serious early warnings. This study could provide a reference for construction planning, management maintenance, and decision-making of marine ranching.

Effect of Fluoride on the Expression of 8-Hydroxy-2'-Deoxyguanosine in the Blood, Kidney, Liver, and Brain of Rats.

Excessive exposure of fluoride not only leads to damage on bone, but also has an adverse effect on soft tissues. Oxidative DNA damage induced by fluoride is thought to be one of the toxic mechanisms of fluoride effect. However, the dose-response of fluoride on oxidative DNA damage is barely studied in organisms. This study investigated the concentration of fluoride in rat blood, kidney, liver, and brain as well as the dose-time effect of fluoride on the expression of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in the above tissues. Rats were exposed to 0 mg/L, 25 mg/L, 50 mg/L, and 100 mg/L of fluorine ion and treated for one and three months. The results showed that the accumulation of fluoride in soft tissues was very different. At the first month, blood fluoride was increased, liver and brain fluoride showed a U-shaped change, and kidney fluoride was not significant. At the third month, blood fluoride was altered with an inverted U-shaped change, kidney and brain fluoride increased, but liver fluoride decreased. Both the exposure concentration and the time of exposure had a significant effect on the expression of 8-OHdG in the above tissues. However, the effect patterns of fluoride on these tissues were notably different at different times. At the first month of fluoride treatment, blood, kidney, and liver 8-OHdG decreased with the increasing fluoride concentration. At the third month, blood 8-OHdG showed a U-shaped change, but kidney 8-OHdG altered with an inverted U-shaped change. Liver 8-OHdG increased, while brain 8-OHdG decreased at the third month. Correlation analysis showed that only blood 8-OHdG was significantly inversely correlated with blood fluoride and dental fluorosis grade in both the first and third months. Liver 8-OHdG was negatively and significantly correlated with liver fluoride. There was a weak but nonsignificant correlation between kidney and brain 8-OHdG and fluoride in both tissues. Additionally, blood 8-OHdG was positively correlated with kidney and liver 8-OHdG at the first month and positively correlated with brain 8-OHdG at the third month. Taken together, our data suggests that concentration and time of fluoride exposure had a significant effect on 8-OHdG, but the effect patterns of fluoride on 8-OHdG were different in the tissues, which suggests that the impact of fluoride on 8-OHdG may be a tissue-specific, as well as a non-monotonic positive correlation.

Assessing Immune Factors in Maternal Milk and Paired Infant Plasma Antibody Binding to Human Rhinoviruses.

Before they can produce their own antibodies, newborns are protected from infections by transplacental transfer of maternal IgG antibodies and after birth through breast milk IgA antibodies. Rhinovirus (RV) infections are extremely common in early childhood, and while RV infections often result in only mild upper respiratory illnesses, they can also cause severe lower respiratory illnesses such as bronchiolitis and pneumonia. We used high-density peptide arrays to profile infant and maternal antibody reactivity to capsid and full proteome sequences of three human RVs - A16, B52, and C11. Numerous plasma IgG and breast milk IgA RV epitopes were identified that localized to regions of the RV capsid surface and interior, and also to several non-structural proteins. While most epitopes were bound by both IgG and IgA, there were several instances where isotype-specific and RV-specific binding were observed. We also profiled 62 unique RV-C dominant protein loop sequences characteristic of this species' capsid VP1 protein. Many of these RV-C sites were highly bound by IgG from one-year-old infants, indicating recent or ongoing active infections, or alternatively, a level of cross-reactivity among homologous RV-C sites.

Milankovitch theory and monsoon.

The widely accepted "Milankovitch theory" explains insolation-induced waxing and waning of the ice sheets and their effect on the global climate on orbital timescales. In the past half century, however, the theory has often come under scrutiny, especially regarding its "100-ka problem." Another drawback, but the one that has received less attention, is the "monsoon problem," which pertains to the exclusion of monsoon dynamics in classic Milankovitch theory even though the monsoon prevails over the vast low-latitude (∼30° N to ∼30° S) region that covers half of the Earth's surface and receives the bulk of solar radiation. In this review, we discuss the major issues with the current form of Milankovitch theory and the progress made at the research forefront. We suggest shifting the emphasis from the ultimate outcomes of the ice volume to the causal relationship between changes in northern high-latitude insolation and ice age termination events (or ice sheet melting rate) to help reconcile the classic "100-ka problem." We discuss the discrepancies associated with the characterization of monsoon dynamics, particularly the so-called "sea-land precession-phase paradox" and the "Chinese 100-ka problem." We suggest that many of these discrepancies are superficial and can be resolved by applying a holistic "monsoon system science" approach. Finally, we propose blending the conventional Kutzbach orbital monsoon hypothesis, which calls for summer insolation forcing of monsoons, with Milankovitch theory to formulate a combined "Milankovitch-Kutzbach hypothesis" that can potentially explain the dual nature of orbital hydrodynamics of the ice sheet and monsoon systems, as well as their interplays and respective relationships with the northern high-latitude insolation and inter-tropical insolation differential.