Dupliumab therapy for alopecia areata: a case series and review of the literature.

BACKGROUND: A growing body of research supports the important role of the TH2 axis in alopecia areata (AA). Dupilumab is a humanized monoclonal antibody against IL-4Rα that downregulates TH2 response. Although efficacy has been shown in clinical trials, real-world data on the use of dupilumab in AA patients is limited. OBJECTIVES: To report on a case series of 10 patients with AA who were treated with dupilumab and provide real-world evidence regarding its efficacy in treating severe AA. METHODS: In this retrospective single-center study, all AA patients treated with dupilumab treatment were included between May 2022 and October 2023. Clinical outcome measures (Severity of Alopecia Tool, SALT) and adverse events (AEs) were analyzed. In addition, a literature review was conducted to summarize the efficacy of AA with dupilumab and the characteristics of patients previously reported in the literature. RESULTS: We identified 10 patients with AA who were or are being treated with dupilumab, with a median (range) treatment duration of 8 (3-15) months. Of these, four patients have high serum immunoglobulin E (IgE) levels (≥200IU/ml). The mean (IQR) pretreatment SALT score was 79% (52-100). Seven of 10 patients achieved at least 50% re-growth. Of those who improved, the mean (IQR) percentage change in SALT score at 3 months and the end of follow-up was 57% (29%-89%) and 95% (68-100), respectively. Notably, seven patients (70%) had white hair regrowth, with the white hair slowly decreasing over time and the proportion of pigmented black hair increasing. Dupilumab was well tolerated by all patients. No adverse events were reported. CONCLUSIONS: Overall, our research supports dupilumab as another candidate that possesses potential benefits for AA. High levels of IgE may be not prerequisites for dupilumab's successful treatment response.

County-based demographics, patterns of treatment seeking, and disease burden for malignant tumor patients in China.

BACKGROUND: The mortality of malignant tumors in rural areas of China in 2015 was significantly higher than that in city areas (213.6 per 100,000 vs. 191.5 per 100,000), bringing huge economic pressure to individuals and the local community. The comprehensive reform of county-level public hospitals in Yun County has helped patients with critical disease receive appropriate treatment. Therefore, an analysis focused on the epidemiology and disease burden of malignant tumors in Yun County could provide guidance for administrators and health practitioners in other counties. METHODS: This retrospective database study extracted data from the Yun County medical community (including two higher level hospitals: Yun County People's Hospital and Yun County Chinese Medicine Hospital, and 13 township central hospitals) from 1st Jul 2017 to 30th Aug 2020. Patients diagnosed as having a malignant tumor were enrolled and those with abnormal key baseline information were excluded. The epidemiology and disease burden for malignant tumor patients were assessed. RESULTS: A total of 3,792 patients were enrolled, and the most prevalent cancer in 2018 was thyroid (35.4 patients/100,000) and in 2019 this was lung cancer (30.6 patients/100,000). The mean outpatient visits per person for all-cause and tumor-specific visits were 9.99 and 3.94 visits across 2018 and 2019, respectively, and the mean inpatient visits per person in both years were the same at 2.56 visits. Total costs were 14.471 and 20.29 million in 2018 and 2019, respectively, and 71.7% and 73.0% of the total cost were covered by medical insurance over the 2 years. CONCLUSIONS: The medical environment has improved since medical system reform commenced in 2019 in Yun County, and medical insurance has decreased the disease burden for patients and their families significantly.

China county-based demographics, clinical characteristics, treatment patterns, and health resource consumption analysis for diabetes.

BACKGROUND: The diagnosis and treatment of diabetes depends on reasonable chronic disease management. Compared with urban areas, county areas are high-risk areas for chronic disease patients, due to the low awareness of chronic disease, poor treatment compliance with chronic disease, low drug persistence, and low cure rate. Therefore, more attention should be paid to chronic disease management in county areas. METHODS: This retrospective, observational study was conducted at the Yun county medical community, Yun county, Yunan province. Data were collected from the medical records of diabetic patients from July 2017 to Aug 2020. The primary outcome variable was the proportion of patients with diabetic complications in county areas. The secondary outcome variables were demographics and clinical characteristics of diabetic patients in county areas, achievement of the HbA1c target, and clinical inertia of diabetic patients in county areas. Comparisons of the simple diabetes group and the diabetic kidney disease (DKD) group in terms of demographics, clinical characteristics, treatment patterns, and health resource consumption were also conducted. A series of appropriate statistical tests were applied to the study population to examine the various outcomes. RESULTS: A total of 9,721 type 2 diabetic patients were included for the study analysis. Diabetic retinopathy (11.83%), cerebrovascular disease (10.31%), and DKD (9.29%) were the 3 most common complications in overall admissions. Among the 1,347 patients with HbA1c test results, 536 (39.8%) patients achieved the HbA1c target, while 566 (87.62%) of the 661 patients who did not achieve the HbA1c target had clinical inertia during the next 6 months. Compared with simple diabetes patients, patients with DKD had a higher age, wider coverage of medical insurance, and longer duration of diabetes, and were more likely to be complicated with hyperuricemia, dyslipidemia, and hypertension. Regular insulin, metformin, alpha-glucosidase inhibitor, and sulfonylurea were the most widely used antidiabetic drugs in patients with DKD. The health resources consumption also significantly increased. CONCLUSIONS: The proportion of complications in diabetic patients is high in county areas, and blood glucose control is still insufficient. Chronic complications are the key reasons for the decrease in quality of life and high medical costs.

Target search kinetics of self-propelled particles in a confining domain.

We present a numerical investigation of the search kinetics of self-propelled particles (SPPs) to a target located at the center or at the boundary of a confining domain. When searching a target located at the center of a circular confining domain, the search efficiency of SPPs is improved compared to that of Brownian particles if the rotational diffusion is not too slow. In this case, the mean search time τ could be minimized with proper combinations of the characteristic rotation time τθ and the self-propulsion velocity v0. It is further shown to be a consequence of the interplay between the enhanced diffusion and the thigmotactism (boundary-following behavior) of SPPs due to the self-propulsion. However, for a target located at the boundary of the circular confining domain, we find that the search process is continuing to be accelerated with increasing τθ or v0. Our results highlight the role of the target position in the search kinetics, and open up new opportunities to optimize the search process of SPPs by taking accurate controls over their motions.

How nonspecifically DNA-binding proteins search for the target in crowded environments.

We investigate how a tracer particle searches a target located in DNA modeled by a stiff chain in crowded environments using theoretical analysis and Langevin dynamics simulations. First, we show that the three-dimensional (3D) diffusion coefficient of the tracer only depends on the density of crowders ϕ, while its one-dimensional (1D) diffusion coefficient is affected by not only ϕ but also the nonspecific binding energy ε. With increasing ϕ and ε, no obvious change in the average 3D diffusion time is observed, while the average 1D sliding time apparently increases. We propose theoretically that the 1D sliding of the tracer along the chain could be well captured by the Kramers' law of escaping rather than the Arrhenius law, which is verified directly by the simulations. Finally, the average search time increases monotonously with an increase in ϕ while it has a minimum as a function of ε, which could be understood from the different behaviors of the average number of search rounds with the increasing ϕ or ε. These results provide a deeper understanding of the role of facilitated diffusion in target search of proteins on DNA in vivo.

Translocation of Rigid Rod-Shaped Virus through Various Solid-State Nanopores.

Nanopores have been used as a high throughput tool for characterizing individual biomolecules and nanoparticles. Here, we present the translocation of rigid rod-shaped tobacco mosaic virus (TMV) through solid-state nanopores. Interestingly, due to the high rigidity of TMV, three types of events with distinctive characteristics at the capture process and a strong current fluctuation during the translocation of TMV are observed. A kinetic model is then proposed to address the dynamics of the translocation, followed by corresponding dynamics simulations. The results reveal that TMV has to rotate to fit and pass the pore when it is captured by a nanopore with an angle larger than the maximum angle that allows it to pass through. Then, we investigate the dependence of the rotation of TMV on the conductance fluctuations at the blockade stage. The results show that the rotation of TMV during the passage through the pore affects the current signal significantly. This study gives a fundamental understanding of the dynamics of rod-shaped particles translocating through the nanopore and how the current responds to it. It opens a new possible way to characterize the rigidity of analytes by nanopores.

Polymer segregation under confinement: Influences of macromolecular crowding and the interaction between the polymer and crowders.

Entropy driven polymer segregation in confinements as a model for chromosome separation in bacteria has attracted wide attention; however, the effects of macromolecular crowding and the interaction between the binding protein and the newly replicated DNA on the segregation dynamics are not clear. Using Langevin dynamics simulations, we investigate the influences of crowders and the attractive interaction between the polymer and a small number of crowders on segregation of two overlapping polymers under a cylindrical confinement. We find that the segregation time increases with increasing the volume fraction of crowders due to the slower chain diffusion in crowded environments. For a fixed volume fraction of crowders, the segregation time decreases with increasing the size of crowders. Moreover, the attractive interaction between the polymer and a small number of crowders can significantly facilitate the chain segregation. These results are important for understanding the chromosome segregation in living cells.

Surface-adsorption-induced polymer translocation through a nanopore: Effects of the adsorption strength and the surface corrugation.

The surface corrugation plays an important role in single polymer diffusion on attractive surfaces. However, its effect on dynamics of surface adsorption-induced polymer translocation through a nanopore is not clear. Using three-dimensional Langevin dynamics simulations, we investigate the dynamics of a flexible polymer chain translocation through a nanopore induced by the selective adsorption of translocated segments onto the trans side of the membrane. The translocation probability Ptrans increases monotonically, while the mean translocation time τ has a minimum as a function of the adsorption strength ɛ, which are explained from the perspective of the effective driving force for the translocation. With the surface being smoother, τ as well as the scaling exponent α of τ with the chain length N decreases. Finally, we show that the distributions of the translocation time are non-Gaussian even for strong adsorption at a moderate surface corrugation. A nearly Gaussian distribution of the translocation time is observed only for the smoothest surface we studied.

Effects of the internal friction and the solvent quality on the dynamics of a polymer chain closure.

Using 3D Langevin dynamics simulations, we investigate the effects of the internal friction and the solvent quality on the dynamics of a polymer chain closure. We show that the chain closure in good solvents is a purely diffusive process. By extrapolation to zero solvent viscosity, we find that the internal friction of a chain plays a non-ignorable role in the dynamics of the chain closure. When the solvent quality changes from good to poor, the mean closure time τc decreases by about 1 order of magnitude for the chain length 20 ≤ N ≤ 100. Furthermore, τc has a minimum as a function of the solvent quality. With increasing the chain length N, the minimum of τc occurs at a better solvent. Finally, the single exponential distributions of the closure time in poor solvents suggest that the negative excluded volume of segments does not alter the nearly Poisson statistical characteristics of the process of the chain closure.

DNA-binding protein searches for its target: Non-monotonic dependence of the search time on the density of roadblocks bound on the DNA chain.

The search of DNA-binding proteins for their target sites positioned on DNA plays a very important role in many cellular processes, and this search process combines 3D excursions in the bulk solution with one-dimensional sliding along the DNA chain. In living cells, there exist roadblocks along DNA chain formed by other proteins; however, the role of the roadblock in search rate is poorly understood. Based on 3D Langevin dynamics simulations, we have investigated the effect of the blocker on the search dynamics. For a pair of symmetrically placed blockers with respect to the target, we find that, with increasing the distance between the blocker and the target, the search time, τ, rapidly decreases and then saturates. For randomly placed blockers with density ϕ, τ may initially increase to its maximum and then unexpectedly decreases with increasing ϕ, or always increase with ϕ, depending on the nonspecific interaction strength and the volume fraction of DNA in the system. The previous contradicted results on the role of the blocker in search time are reconciled by these findings. Particularly, the nonmonotonic behavior of τ with ϕ indicates that blockers may facilitate the search after a critical ϕ.

Dynamics of polymer translocation through kinked nanopores.

Polymer translocation through nanopore has potential technological applications for DNA sequencing, where one challenge problem is to slow down translocation speed. Inspired by experimental findings that kinked nanopores exhibit a large reduction in translocation velocity compared with their straight counterparts, we investigate the dynamics of polymer translocation through kinked nanopores in two dimensions under an applied external field. With increasing the tortuosity of an array of nanopores, our analytical results show that the translocation probability decreases. Langevin dynamics simulation results support this prediction and further indicate that with increasing the tortuosity, translocation time shows a slow increase followed by a rapid increase after a critical tortuosity. This behavior demonstrates that kinked nanopores can effectively reduce translocation speed. These results are interpreted by the roles of the tortuosity for decreasing the effective nanopore diameter, increasing effective nanopore length, and greatly increasing the DNA-pore friction.

Molecular crowding effect on dynamics of DNA-binding proteins search for their targets.

DNA-binding proteins locate and bind their target sequences positioned on DNA in crowded environments, but the molecular crowding effect on this search process is not clear. Using analytical techniques and Langevin dynamics simulations in two dimensions (2D), we find that the essential physics for facilitated diffusion in 2D search and 3D search is the same. We observe that the average search times have minima at the same optimal nonspecific binding energy for the cases with and without the crowding particle. Moreover, the molecular crowding increases the search time by increasing the average search rounds and the one-dimensional (1D) sliding time of a round, but almost not changing the average 2D diffusion time of a round. In addition, the fraction of 1D sliding time out of the total search time increases with increasing the concentration of crowders. For 2D diffusion, the molecular crowding decreases the jumping length and narrows its distribution due to the cage effect from crowders. These results shed light on the role of facilitated diffusion in DNA targeting kinetics in living cells.

Polymer translocation through a nanopore driven by binding particles: influence of chain rigidity.

We investigate the influence of chain rigidity on the dynamics of polymer translocation in the presence of binding particles (BPs) through a nanopore using two-dimensional Langevin dynamics simulations. With increasing chain rigidity κ, the mean translocation time 〈τ〉 increases monotonically due to an increase in the radius of gyration and a decrease in the center of mass velocity. Particularly for weak binding, we further find that 〈τ〉 shows a power-law behavior with the persistence length lp. Analysis indicates a scaling relation between the average velocity of the center of mass of a chain 〈vc.m.〉 and lp. As the chain becomes stiffer, the distribution of the translocation time τ approximates the Gaussian distribution and gets broader with the peak position being shifted towards longer translocation time. The corresponding translocation coordinate smax of the maximum waiting time gets smaller with increasing chain rigidity. Finally, under an extremely low BP concentration, 〈τ〉 shows a minimum for small κ, while it decreases monotonically for large κ with increasing binding energy. Our results suggest a nontrivial effect of the intrinsic property of chains on the dynamics of polymer translocation driven by BPs.

Surface modification of solid-state nanopores for sticky-free translocation of single-stranded DNA.

Nanopore technology is one of the most promising approaches for fast and low-cost DNA sequencing application. Single-stranded DNA detection is primary objective in such device, while solid-state nanopores remain less explored than their biological counterparts due to bio-molecule clogging issue caused by surface interaction between DNA and nanopore wall. By surface coating a layer of polyethylene glycol (PEG), solid-state nanopore can achieve long lifetime for single-stranded DNA sticky-free translocation at pH 11.5. Associated with elimination of non-specific binding of molecule, PEG coated nanopore presents new surface characteristic as less hydrophility, lower 1/f noise, and passivated surface charge responsiveness on pH. Meanwhile, conductance blockage of single-stranded DNA is found to be deeper than double-stranded DNA, which can be well described by a string of blobs model for a quasi-equilibrium state polymer in constraint space.

Polymer translocation into a confined space: influence of the chain stiffness and the shape of the confinement.

Using two-dimensional Langevin dynamics simulations, we investigate the dynamics of polymer translocation into a confined space under a driving force through a nanopore, with particular emphasis on the chain stiffness and the shape of the confinement. We observe that with increasing the chain stiffness κ, the translocation time τ always increases for different shapes of confinements. For an ellipse, τ is different for the translocation through its minor and major axis directions. Under the weak confinement, the translocation through the minor axis direction is faster than that through the major axis direction for different κ, while this is true only for high κ under strong confinement. Particularly, for both weak and strong confinements we find that packaging into an ellipse through its minor axis direction is faster than that for a circle of the same area for high κ. These results are interpreted by the chain conformation during the translocation process and the time of an individual segment passing through the pore.

Polyprodrug amphiphiles: hierarchical assemblies for shape-regulated cellular internalization, trafficking, and drug delivery.

Solution self-assembly of block copolymers (BCPs) typically generates spheres, rods, and vesicles. The reproducible bottom-up fabrication of stable planar nanostructures remains elusive due to their tendency to bend into closed bilayers. This morphological vacancy renders the study of shape effects on BCP nanocarrier-cell interactions incomplete. Furthermore, the fabrication of single BCP assemblies with built-in drug delivery functions and geometry-optimized performance remains a major challenge. We demonstrate that PEG-b-PCPTM polyprodrug amphiphiles, where PEG is poly(ethylene glycol) and PCPTM is polymerized block of reduction-cleavable camptothecin (CPT) prodrug monomer, with >50 wt % CPT loading content can self-assemble into four types of uniform nanostructures including spheres, large compound vesicles, smooth disks, and unprecedented staggered lamellae with spiked periphery. Staggered lamellae outperform the other three nanostructure types, exhibiting extended blood circulation duration, the fastest cellular uptake, and unique internalization pathways. We also explore shape-modulated CPT release kinetics, nanostructure degradation, and in vitro cytotoxicities. The controlled hierarchical organization of polyprodrug amphiphiles and shape-tunable biological performance opens up new horizons for exploring next-generation BCP-based drug delivery systems with improved efficacy.

Dynamics of polymer translocation through a nanopore induced by different sizes of crowding agents.

Using both theoretical analysis and Langevin dynamics simulations in two dimensions, we investigate the dynamics of polymer translocation through a nanopore induced by different sizes of the mobile crowding agents, where the crowding agents have equal area fraction φ and their diameters are σ and σb ≥ σ at cis and trans sides, respectively. The chain prefers moving to the side with bigger crowding agents as expected, however, we find the size difference between crowding agents plays a complicated role in the probability of polymer translocation from cis to trans side, the translocation time τ and its distribution, and the translocation exponent. In particular, with increasing σb, the translocation probability shows a maximum value and τ has a minimum value. These results can be interpreted by the effective driving force, which always increases with increasing φ but has a maximum value with increasing σb.

Chain conformation of ring polymers under a cylindrical nanochannel confinement.

We investigate the chain conformation of ring polymers confined to a cylindrical nanochannel using both theoretical analysis and three-dimensional Langevin dynamics simulations. We predict that the longitudinal size of a ring polymer scales with the chain length and the diameter of the channel in the same manner as that for linear chains based on scaling analysis and Flory-type theory. Moreover, Flory-type theory also gives the ratio of the longitudinal sizes for a ring polymer and a linear chain with identical chain length. These theoretical predictions are confirmed by numerical simulations. Finally, our simulation results show that this ratio first decreases and then saturates with increasing the chain stiffness, which explains the discrepancy in experiments. Our results have biological significance.

Dynamics of polymer translocation into a circular nanocontainer through a nanopore.

Using Langevin dynamics simulations, we investigate the dynamics of polymer translocation into a circular nanocontainer through a nanopore under a driving force F. We observe that the translocation probability initially increases and then saturates with increasing F, independent of φ, which is the average density of the whole chain in the nanocontainer. The translocation time distribution undergoes a transition from a Gaussian distribution to an asymmetric distribution with increasing φ. Moreover, we find a nonuniversal scaling exponent of the translocation time as chain length, depending on φ and F. These results are interpreted by the conformation of the translocated chain in the nanocontainer and the time of an individual segment passing through the pore during translocation.

Translocation of stiff polymers through a nanopore driven by binding particles.

We investigate the translocation of stiff polymers in the presence of binding particles through a nanopore by two-dimensional Langevin dynamics simulations. We find that the mean translocation time shows a minimum as a function of the binding energy ε and the particle concentration φ, due to the interplay of the force from binding and the frictional force. Particularly, for the strong binding the translocation proceeds with a decreasing translocation velocity induced by a significant increase of the frictional force. In addition, both ε and φ have a notable impact on the distribution of the translocation time. With increasing ε and φ, it undergoes a transition from an asymmetric and broad distribution under the weak binding to a nearly Gaussian one under the strong binding, and its width becomes gradually narrower.