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Abstract BACKGROUNDThe strongest genetic drivers of late‐onset Alzheimer's disease (AD) are apolipoprotein E4 (ApoE4) and TREM2^R47H. Despite their critical roles, the mechanisms underlying their interactions remain poorly understood. METHODSWe conducted microsecond‐long molecular dynamics simulations of TREM2‐ApoE complexes, including TREM2^R47H, validating our findings through comparison with published experimental data on TREM2‐ApoE binding interactions. RESULTSOur simulations reveal TREM2^WTcan sample an “open” CDR2 conformation, challenging the prevailing notion that this conformation is pathogenic. TREM2^WTexhibits greater flexibility, accessing diverse CDR2 conformations, while rigidity in TREM2^R47H’s CDR2 may explain its reduced ligand‐binding properties. ApoE2 facilitates dynamic reconfiguration of TREM2‐ApoE2 complexes, which is absent with ApoE4. TREM2^R47Hand ApoE4 mutually rigidify each other, suppressing interfacial flexibility. DISCUSSIONOur findings suggest mechanisms underlying ApoE2's neuroprotective functions, ApoE4's pathogenicity, and the synergistic effects of ApoE4 and TREM2^R47Hin AD. TREM2^WT’s flexibility and reconfiguration with ApoE2 may support microglial activation, while rigidity in TREM2^R47H‐ApoE4 interactions may drive pathogenic signaling. HighlightsTREM2^WTsamples diverse CDR2 conformations, challenging prior assumptions that an “open” CDR2 state is solely pathogenic.ApoE2 promotes dynamic reconfiguration of TREM2‐ApoE2 complexes, preserving TREM2^WT's flexibility.ApoE4's hinge forms a unique binding pocket that enhances TREM2 binding.The TREM2^R47H‐ApoE4 complex exhibits mutual rigidity, suppressing CDR2 and hinge flexibility. 

Abstract Polymeric micro‐ and nanoparticles are useful vehicles for delivering cytokines to diseased tissues such as solid tumors. Double emulsion solvent evaporation is one of the most common techniques to formulate cytokines into vehicles made from hydrophobic polymers; however, the liquid–liquid interfaces formed during emulsification can greatly affect the stability and therapeutic performance of encapsulated cytokines. To develop more effective cytokine‐delivery systems, a clear molecular understanding of the interactions between relevant proteins and solvents used in the preparation of such particles is needed. We utilized an integrated computational and experimental approach for studying the governing mechanisms by which interleukin‐12 (IL‐12), a clinically relevant cytokine, is protected from denaturation by albumin, a common stabilizing protein, at an organic‐aqueous solvent interface formed during double emulsification. We investigated protein–protein interactions between human (h)IL‐12 and albumin and simulated these components in pure water, dichloromethane (DCM), and along a water/DCM interface to replicate the solvent regimes formed during double emulsification. We observed that (i) hIL‐12 experiences increased structural deviations near the water/DCM interface, and (ii) hIL‐12 structural deviations are reduced in the presence of albumin. Experimentally, we found that hIL‐12 bioactivity is retained when released from particles in which albumin is added to the aqueous phase in molar excess to hIL‐12 and sufficient time is allowed for albumin‐hIL‐12 binding. Findings from this work have implications in establishing design principles to enhance the stability of cytokines and other unstable proteins in particles formed by double emulsification for improved stability and therapeutic efficacy. 

Sunlight breaks down dissolved organic matter (DOM) in lakes and streams to produce carbon dioxide (a greenhouse gas). The efficiency of this process depends on light exposure, the aromatic content of DOM (i.e., Ar–C), and dissolved iron (Fe). 

Abstract The microglial surface protein Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) plays a critical role in mediating brain homeostasis and inflammatory responses in Alzheimer’s disease (AD). The soluble form of TREM2 (sTREM2) exhibits neuroprotective effects in AD, though the underlying mechanisms remain elusive. Moreover, differences in ligand binding between TREM2 and sTREM2, which have major implications for their roles in AD pathology, remain unexplained. To address these knowledge gaps, we conducted the most computationally intensive molecular dynamics simulations to date of (s)TREM2, exploring their interactions with key damage- and lipoprotein-associated phospholipids and the impact of the AD-risk mutation R47H. Our results demonstrate that the flexible stalk domain of sTREM2 serves as the molecular basis for differential ligand binding between sTREM2 and TREM2, facilitated by its role in stabilizing the Ig-like domain and altering the accessibility of canonical ligand binding sites. We identified a novel ligand binding site on sTREM2, termed the ‘Expanded Surface 2’, which emerges due to competitive binding of the stalk with the Ig-like domain. Additionally, we observed that the stalk domain itself functions as a site for ligand binding, with increased binding in the presence of R47H. This suggests that sTREM2’s neuroprotective role in AD may, at least in part, arise from the stalk domain’s ability to rescue dysfunctional ligand binding caused by AD-risk mutations. Lastly, our findings indicate that R47H-induced dysfunction in membrane-bound TREM2 may result from both diminished ligand binding due to restricted complementarity-determining region 2 loop motions and an impaired ability to differentiate between ligands, proposing a novel mechanism for loss-of-function. In summary, these results provide valuable insights into the role of sTREM2 in AD pathology, laying the groundwork for the design of new therapeutic approaches targeting (s)TREM2 in AD. 

STEM Intervention Programs (SIPs) can influence student persistence in science. A survey measured multiple persistence factors among STEM students at one non-traditional university and focus groups triangulated nuances of the student experience. Overall, students in SIPs are more likely to persist and experience belonging. 

Rhabdophane is a hydrous phosphate that commonly replaces monazite as a weathering product in critical mineral deposits during the alteration of rare earth elements (REE) bearing carbonatites and alkaline igneous complexes. It is an important host to the light (L)REE (i.e., La to Gd) but the stability and structure of binary solid solutions between the Ce and the other LREE endmembers have not yet been determined experimentally. Here we present room temperature calorimetric experiments that were used to measure the enthalpy of precipitation of rhabdophane (Ce1−xREExPO4·nH2O; REE = La, Pr, Nd, Sm, Eu, and Gd). The solids were characterized using X-ray diffraction, scanning electron microscopy, Raman spectroscopy, and the role of water in the rhabdophane structure was further determined using thermogravimetric analysis coupled with differential scanning calorimetry. The calorimetric experiments indicate a non-ideal behavior for all of the binary solid solutions investigated with an excess enthalpy of mixing (ΔHex) described by a 2- to 3-term Guggenheim parameters equation. The solid solutions were categorized into three groups: (1) binary Ce-La and Ce-Pr which display positive ΔHex values with a slight asymmetry; (2) binary Ce-Nd and Ce-Sm which display negative ΔHex values with a nearly symmetric shape; (3) Ce-Eu and Ce-Gd which display both negative and positive ΔHex values with nearly symmetric shape. The excess Gibbs energy (ΔGex) of the solid solutions was further investigated using a thermodynamic analysis approach of aqueous-solid solution equilibria and the optimization programs GEMS and GEMSFITS. The resulting ΔGex values combined with the calorimetric ΔHex values indicate that there is likely an excess entropy contribution implying important short-range structural modifications in the solid solutions dependent on the deviation of the REE ionic radii from the size of Ce3+. These observations corroborate with the trends in the Raman v1 stretching bands of the PO4-site. The excess molar volumes determined from X-ray diffraction analysis further indicate an overall asymmetric behavior in all of the studied binary solid solutions, which becomes increasingly important from La to Gd. The pronounced short-range order–disorder occurring in groups 2 and 3 solid solutions mimics some of the behavior observed from previous studies in anhydrous monazite solid solutions. This study highlights the potential to use the chemistry and the structural modifications of rhabdophane as potential indicators of formation conditions in geologic systems and permits improving our modeling capabilities of REE partitioning in critical minerals systems. 

ABSTRACT Here, we report on the raw and coassembled metatranscriptomes of 39 Lake Erie surface (1.0 m) water samples collected over a 2-day diel period encompassing episodic weather and bloom events. Preliminary taxonomic annotations and read mappings revealed thatMicrocystisspp. accounted for up to ~47% of the transcriptionally active community. 

Teaching assistants (TA) have increasingly been tasked with facilitating course-based undergraduate research experiences (CUREs). Yet, there is little discussion in the literature regarding the need for or approaches to providing professional development (PD) for this population. This essay is a “call to action” for promoting intentional CURE TA PD.