Table_1_Case Report: TNF-Alpha Inhibitors to Rescue Pregnancy in Women With Potential Pregnancy Loss: A Report of Ten Cases.xlsx

Miscarriage poses a significant threat to pregnant women globally. Recurrent miscarriages or potential poor embryonic development indicated by early drops in serum human chorionic gonadotrophin (hCG) are even more catastrophic for pregnant women. However, these patients receive either individualized medical intervention supported by limited evidence or no treatment at all. In this study, we report ten patients who shared at least one episode of an early decline of hCG in the first trimester and were treated with compassionate use of tumor necrosis factor-alpha inhibitor (TNFi). They were then followed up regularly with caution. Their hCG trajectory all resumed a normal pattern within one week and the obstetric outcomes were promising. No adverse fetal, neonatal, or maternal health issues have been observed. This case series supports current safety evidence of TNFi and provides new insight into its use in pregnancy when the embryo is in danger. Further well-designed clinical trials should be carried out to consolidate the evidence.</p

Rational Design of Metal Halide Perovskite Nanocrystals for Photocatalytic CO₂ Reduction: Recent Advances, Challenges, and Prospects

Metal halide perovskite nanocrystals (MHP NCs) have attracted much scientific interest in photocatalysis. Various types of MHP photocatalysts have been intensively explored in photocatalytic CO2 reduction in the past few years. However, some key issues, such as severe charge recombination, low stability, and the origin of products, have created bottlenecks in developing MHP photocatalysts. Therefore, the rational design of MHPs is worthwhile to deepen our understanding of the above issues and develop efficient photocatalysts. This Focus Review highlights the recent advances in MHP photocatalysts regarding design principles toward photocatalytic CO2 reduction. Various modification strategies are clarified, and an outlook on future challenges and prospects is also provided to point out the possible research directions in MHP photocatalysts. It is anticipated that this Focus Review can provide guidance on the design of MHP-based photocatalysts and help uncover some common issues encountered by the scientific community when studying MHP photocatalysts

In-cell binding of mHsp70 and ePGKs.

Filled markers and dashed lines show experimental data and solid lines are fits to experimental data. Error bars are standard error from mean for 15–30 cells. Fit errors reflect the 1 standard deviation precision of the fit. FRET efficiency average for (a) mHsp70- and (b) mHsp70K71M-PGK binding vs. temperature for ePGK0 (black), ePGK1 (dark red), ePGK2 (red) and ePGK3 (orange).</p

<i>In vitro</i> binding of 1:1 mHsp70 and ePGKs with and without cell lysate.

Filled markers show experimental data and solid lines are fits to experimental data. Error bars are standard error from mean for two measurement repeats. Fit errors reflect the 1 standard deviation precision of the fit. Binding of ePGK0 (black), ePGK1 (dark red), ePGK2 (red) and ePGK3 (orange) in buffer with (A) Ficoll70, ATP and Hsp40 with mHsp70 without cell lysate and (B) Ficoll70, cell lysate, ATP and Hsp40 with mHsp70.</p

Presentation_1_Case Report: TNF-Alpha Inhibitors to Rescue Pregnancy in Women With Potential Pregnancy Loss: A Report of Ten Cases.pptx

Miscarriage poses a significant threat to pregnant women globally. Recurrent miscarriages or potential poor embryonic development indicated by early drops in serum human chorionic gonadotrophin (hCG) are even more catastrophic for pregnant women. However, these patients receive either individualized medical intervention supported by limited evidence or no treatment at all. In this study, we report ten patients who shared at least one episode of an early decline of hCG in the first trimester and were treated with compassionate use of tumor necrosis factor-alpha inhibitor (TNFi). They were then followed up regularly with caution. Their hCG trajectory all resumed a normal pattern within one week and the obstetric outcomes were promising. No adverse fetal, neonatal, or maternal health issues have been observed. This case series supports current safety evidence of TNFi and provides new insight into its use in pregnancy when the embryo is in danger. Further well-designed clinical trials should be carried out to consolidate the evidence.</p

<i>In vitro</i> FRET-PGK1 refolding assay with Hsp70.

Markers show experimental data and solid lines show fits to experimental data. Data displayed was binned at 1 second time intervals.</p

Heat shock-induced chaperoning by Hsp70 is enabled in-cell

Recent work has shown that weak protein-protein interactions are susceptible to the cellular milieu. One case in point is the binding of heat shock proteins (Hsps) to substrate proteins in cells under stress. Upregulation of the Hsp70 chaperone machinery at elevated temperature was discovered in the 1960s, and more recent studies have shown that ATPase activity in one Hsp70 domain is essential for control of substrate binding by the other Hsp70 domain. Although there are several denaturant-based assays of Hsp70 activity, reports of ATP-dependent binding of Hsp70 to a globular protein substrate under heat shock are scarce. Here we show that binding of heat-inducible Hsp70 to phosphoglycerate kinase (PGK) is remarkably different in vitro compared to in-cell. We use fluorescent-labeled mHsp70 and ePGK, and begin by showing that mHsp70 passes the standard β-galactosidase assay, and that it does not self-aggregate until 50°C in presence of ATP. Yet during denaturant refolding or during in vitro heat shock, mHsp70 shows only ATP-independent non-specific sticking to ePGK, as evidenced by nearly identical results with an ATPase activity-deficient K71M mutant of Hsp70 as a control. Addition of Hsp40 (co-factor) or Ficoll (crowder) does not reduce non-specific sticking, but cell lysate does. Therefore, Hsp70 does not act as an ATP-dependent chaperone on its substrate PGK in vitro. In contrast, we observe only specific ATP-dependent binding of mHsp70 to ePGK in mammalian cells, when compared to the inactive Hsp70 K71M mutant. We hypothesize that enhanced in-cell activity is not due to an unknown co-factor, but simply to a favorable shift in binding equilibrium caused by the combination of crowding and osmolyte/macromolecular interactions present in the cell. One candidate mechanism for such a favorable shift in binding equilibrium is the proven ability of Hsp70 to bind near-native states of substrate proteins in vitro. We show evidence for early onset of binding in-cell. Our results suggest that Hsp70 binds PGK preemptively, prior to its full unfolding transition, thus stabilizing it against further unfolding. We propose a “preemptive holdase” mechanism for Hsp70-substrate binding. Given our result for PGK, more proteins than one might think based on in vitro assays may be chaperoned by Hsp70 in vivo. The cellular environment thus plays an important role in maintaining proper Hsp70 function.</div

DataSheet1_Reduction-responsive supramolecular hybridized paclitaxel nanoparticles for tumor treatment.docx

Powerful chemotherapeutics have been used to combat tumor cells, but serious adverse effects and poor therapeutic efficiency restrict their clinical performance. Herein, we developed reduction-responsive supramolecular hybridized paclitaxel nanoparticles (PTX@HOMNs) for improved tumor treatment. The nanocarrier is composed of F127 and strengthened by a disulfide bond linked organosilica network, which ensures the desirable stability during blood circulation and controlled drug release at tumor sites. The as-prepared PTX@HOMNs could effectively accumulate at tumor regions. After entering tumor cells, PTX@HOMNs can respond to intracellular glutathione, and trigger active drug release for chemotherapy. As a result, PTX@HOMNs exhibited potent antitumor activity against ovarian tumors in vitro and in vivo. Our work provides a deep insight into constructing simple and controlled drug delivery nanoplatforms for improved tumor treatment.</p

Cell Volume Controls Protein Stability and Compactness of the Unfolded State

Macromolecular crowding is widely accepted as one of the factors that can alter protein stability, structure, and function inside cells. Less often considered is that crowding can be dynamic: as cell volume changes, either as a result of external duress or in the course of the cell cycle, water moves in or out through membrane channels, and crowding changes in tune. Both theory and in vitro experiments predict that protein stability will be altered as a result of crowding changes. However, it is unclear how much the structural ensemble is altered as crowding changes in the cell. To test this, we look at the response of a FRET-labeled kinase to osmotically induced volume changes in live cells. We examine both the folded and unfolded states of the kinase by changing the temperature of the media surrounding the cell. Our data reveals that crowding compacts the structure of its unfolded ensemble but stabilizes the folded protein. We propose that the structure of proteins lacking a rigid, well-defined tertiary structure could be highly sensitive to both increases and decreases in cell volume. Our findings present a possible mechanism for disordered proteins to act as sensors and actuators of cell cycle or external stress events that coincide with a change in macromolecular crowding