While many approaches to predict aqueous pKa values exist, the fast and accurate prediction of non‐aqueous pKa values is still challenging. Based on the iBonD experimental pKa database (39 solvents), ...a holistic pKa prediction model was established using machine learning. Structural and physical‐organic‐parameter‐based descriptors (SPOC) were introduced to represent the electronic and structural features of the molecules. The models trained with a neural network or the XGBoost algorithm showed the best prediction performance with a low MAE value of 0.87 pKa units. The approach allows a comprehensive mapping of all possible pKa correlations between different solvents and it was validated by predicting the aqueous pKa and micro‐pKa of pharmaceutical molecules and pKa values of organocatalysts in DMSO and MeCN with high accuracy. An online prediction platform was constructed based on the current model, which can provide pKa prediction for different types of X−H acidity in the most commonly used solvents.
Deep learning enables the holistic pKa prediction of various types of X−H acidities in 39 types of solvents. The accuracy of the predictions is demonstrated by a mean absolute error of 0.87 pKa units.
Objectives
3,4-Dihydroxybutyric acid (3,4-DHBA) is a multifunctional C4 platform compound widely used for the synthesis of various materials, including pharmaceuticals. Although, a biosynthetic ...pathway for 3,4-DHBA production has been developed, its low yield still precludes large-scale use. Here, a heterologous four-step biosynthetic pathway was established in recombinant
Escherichia coli
(
E. coli
) using a combinatorial strategy.
Results
Several aldehyde dehydrogenases (ALDHs) were screened, using in vitro enzyme assays, to identify suitable catalysts for the dehydrogenation of 3,4-dihydroxybutanal (3,4-DHB) to 3,4-DHBA. A pathway containing glucose dehydrogenase (
Bs
GDH) from
Bacillus subtilis
,
d
-xylonate dehydratase (YagF) from
E. coli
, benzoylformate decarboxylase (
Pp
MdlC) from
Pseudomonas putida
and ALDH was introduced into
E. coli
, generating 3.04 g/L 3,4-DHBA from
d
-xylose (0.190 g 3,4-DHBA/g
d
-xylose). Disruption of competing pathways by deleting
xylA
,
ghrA
,
ghrB
and
adhP
contributed to an 87% increase in 3,4-DHBA accumulation. Expression of a fusion construct containing
Pp
MdlC and YagF enhanced the 3,4-DHBA titer, producing the highest titer and yield reported thus far (7.71 g/L; 0.482 g 3,4-DHBA/g
d
-xylose).
Conclusions
These results showed that deleting genes from competing pathways and constructing fusion proteins significantly improved the titer and yield of 3,4-DHBA in engineered
E. coli
.
Single-nucleotide polymorphisms (SNPs), as disease-related biogenetic markers, are crucial in elucidating complex disease susceptibility and pathogenesis. Due to computational inefficiency, it is ...difficult to identify high-dimensional SNP interactions efficiently using combinatorial search methods, so the spherical evolutionary multi-objective (SEMO) algorithm for detecting multi-locus SNP interactions was proposed. The algorithm uses a spherical search factor and a feedback mechanism of excellent individual history memory to enhance the balance between search and acquisition. Moreover, a multi-objective fitness function based on the decomposition idea was used to evaluate the associations by combining two functions, K2-Score and LR-Score, as an objective function for the algorithm's evolutionary iterations. The performance evaluation of SEMO was compared with six state-of-the-art algorithms on a simulated dataset. The results showed that SEMO outperforms the comparative methods by detecting SNP interactions quickly and accurately with a shorter average run time. The SEMO algorithm was applied to the Wellcome Trust Case Control Consortium (WTCCC) breast cancer dataset and detected two- and three-point SNP interactions that were significantly associated with breast cancer, confirming the effectiveness of the algorithm. New combinations of SNPs associated with breast cancer were also identified, which will provide a new way to detect SNP interactions quickly and accurately.
Cervical cancer is the fourth most common cancer in women. Early detection and diagnosis play an important role in secondary prevention of cervical cancer. This study aims to provide more information ...to develop an effective strategy for the prevention and control of cervical cancer in northern China.
A retrospective single-centre descriptive cross-sectional study was conducted in Chinese PLA General Hospital located in Beijing, covering the period from January 2009 to June 2019. The patients who underwent a polymerase chain reaction (PCR)-based HPV genotyping test and cervical pathological diagnosis were included. Furthermore, we limited the interval between the two examination within 180 days for the purpose of making sure their correlation to analyse their relationship. Moreover, the relationship between different cervical lesions and age as well as single/multiple HPV infection was assessed.
A total of 3134 patients were eligible in this study after HPV genotyping test and pathological diagnosis. Most of the patients (95%) were from northern China. Among the patients, 1745(55.68%) had high-grade squamous intraepithelial neoplasia (HSIL), 1354 (43.20%) had low-grade squamous intraepithelial neoplasia (LSIL) and 35 (1.12%) were Normal. The mean age was 42.06 ± 10.82(range, 17-79 years). The women aged 35-49 years accounted for the highest incidence rate. The top five most commonly identified HPV genotypes in each lesion class were as follows: HPV16, 58, 52, 31 and 51 in the class of HSIL; HPV16, 52, 58, 56 and 51 in the class of LSIL; HPV16, 31, 6,11, 52 and 58 in the class of normal. The frequencies of HPV single genotype infection and multiple genotypes infection were 55.26 and 34.18%, respectively. There was no difference in the attributable proportions of multiple genotypes infection amongst HSIL, LSIL and Normal.
In Northern China, HPV16 was the most dominant genotype in the patients with pathological examination. The peak age of the onset of HSIL was between 35 and 49 years of age. Infection with multiple HPV genotypes did not increase the risk of HSIL. Type-specific HPV prevalence and attribution proportion to cervical precancerous lesions should be taken into consideration in the development of vaccines and strategy for screening in this population.
In this study, 3-benzoylisoxazolines were synthesized by reacting alkenes with various α-nitroketones using chloramine-T as the base. The scope of α-nitroketones and alkenes is extensive, including ...different alkenes and alkynes to form various isoxazolines and isoxazoles. The use of chloramine-T, as the low-cost, easily handled, moderate base for 1,3-dipolar cycloaddition is attractive.
Auditory and verbal abilities of children with early cochlear implant (CI) surgery usually take some time to develop, and a reference index of early development for horizontal comparisons is urgently ...needed to guide the mapping process and adjust rehabilitation programs. Therefore, the aim of this study was to establish a reference value for early auditory preverbal skills development in children with CI and investigate the developmental curve and influencing factors for these children. The LittlEARS® Auditory Questionnaire (LEAQ) scores of 287 eligible Chinese participants were obtained at 1, 2, 3, 6, 9, 12, 18, 24, 28, and 36 months interval after CI activation. The median and standard deviation of the LEAQ score of each hearing stage for these children with different activation ages were calculated to establish the reference values. Quadratic regression was conducted to fit the expected developmental curve of the LEAQ score (
y
=
−
0.057
x
2
+
2.55
x
+
5.45
0 to 20 months). With a linear mixed-effects model, we found that the receptive auditory behavior increased rapidly after CI activation, while expressive language skills developed at a steady rate. We also found that the following factors all significantly influenced the LEAQ: the duration of CI use, the development quotient, age of implantation and activation, and the presence of large vestibular aqueduct syndrome or auditory neuropathy spectrum disorder. The reference values and the expected developmental curve for the LEAQ in children with CI established by the present study provides guidance to clinicians and parents as well as realistic expectations regarding language and speech outcomes.
Vascular-targeted photodynamic therapy (V-PDT) is an effective treatment for port wine stains (PWS). However, repeated treatment is usually needed to achieve optimal treatment outcomes, possibly due ...to the limited treatment light penetration depth in the PWS lesion. The optical clearing technique can increase light penetration in depth by reducing light scattering. This study aimed to investigate the V-PDT in combination with an optical clearing agent (OCA) for the therapeutic enhancement of V-PDT in the rodent skinfold window chamber model. Vascular responses were closely monitored with laser speckle contrast imaging (LSCI), optical coherence tomography angiography, and stereo microscope before, during, and after the treatment. We further quantitatively demonstrated the effects of V-PDT in combination with OCA on the blood flow and blood vessel size of skin microvasculature. The combination of OCA and V-PDT resulted in significant vascular damage, including vasoconstriction and the reduction of blood flow. Our results indicate the promising potential of OCA for enhancing V-PDT for treating vascular-related diseases, including PWS.
Photobiomodulation (PBM) promoting wound healing has been demonstrated by many studies. Currently, 630 nm and 810 nm light-emitting diodes (LEDs), as light sources, are frequently used in the ...treatment of diabetic foot ulcers (DFUs) in clinics. However, the dose–effect relationship of LED-mediated PBM is not fully understood. Furthermore, among the 630
nm and 810
nm LEDs, which one gets a better effect on accelerating the wound healing of diabetic ulcers is not clear. The aim of this study is to evaluate and compare the effects of 630
nm and 810
nm LED-mediated PBM in wound healing both in vitro and in vivo. Our results showed that both 630
nm and 810
nm LED irradiation significantly promoted the proliferation of mouse fibroblast cells (L929) at different light irradiances (1, 5, and 10
mW/cm
2
)
. The cell proliferation rate increased with the extension of irradiation time (100, 200, and 500
s), but it decreased when the irradiation time was over 500
s. Both 630
nm and 810
nm LED irradiation (5
mW/cm
2
)
significantly improved the migration capability of L929 cells. No difference between 630
nm and 810
nm LED-mediated PBM in promoting cell proliferation and migration was detected. In vivo results presented that both 630
nm and 810
nm LED irradiation promoted the wound healing and the expression of the vascular endothelial growth factor (VEGF) and transforming growth factor (TGF) in the wounded skin of type 2 diabetic mice. Overall, these results suggested that LED-mediated PBM promotes wound healing of diabetic mice through promoting fibroblast cell proliferation, migration, and the expression of growth factors in the wounded skin. LEDs (630
nm and 810
nm) have a similar outcome in promoting wound healing of type 2 diabetic mice.
Dielectric barrier discharge in air at atmospheric pressure is produced using nanosecond pulsed supply. The effects of airflows on the discharge characteristics, such as discharge current, breakdown ...voltage, discharge uniformity, and luminous intensity, are investigated at different discharge gaps and pulse repetitive rates. The peak value of the primary discharge current is increased and the luminous intensity is decreased when the airflow rate increases from 0 to 10 m/s at any discharge gap and pulse repetitive frequency. At 1200-Hz pulse repetitive rate, the discharge becomes more uniform at the bigger discharge gap and the breakdown voltage increases when airflow is introduced into the discharge gap. However, at 100-Hz pulse repetitive rate, the discharge uniformity does not change and breakdown voltage decreases when airflow is introduced into the discharge gap. The experimental results also show that the discharge characteristics have significant changes with the airflow rate increasing from 0 to 10 m/s, while almost no obvious change is observed with the airflow rate increasing from 10 to 30 m/s.
While many approaches to predict aqueous pK
values exist, the fast and accurate prediction of non-aqueous pK
values is still challenging. Based on the iBonD experimental pK
database (39 solvents), a ...holistic pK
prediction model was established using machine learning. Structural and physical-organic-parameter-based descriptors (SPOC) were introduced to represent the electronic and structural features of the molecules. The models trained with a neural network or the XGBoost algorithm showed the best prediction performance with a low MAE value of 0.87 pK
units. The approach allows a comprehensive mapping of all possible pK
correlations between different solvents and it was validated by predicting the aqueous pK
and micro-pK
of pharmaceutical molecules and pK
values of organocatalysts in DMSO and MeCN with high accuracy. An online prediction platform was constructed based on the current model, which can provide pK
prediction for different types of X-H acidity in the most commonly used solvents.
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