bluuebunny/crossref_metadata_2025 huggingface dataset:
Wettability gradient-driven droplets with an applied external force
Authors: Topp Leon , Haddick Lena , Mählmann Dominik , Heuer Andreas
Published: May 2023

On homogeneous substrates, droplets can slide due to external driving forces, such as gravity, whereas in the presence of wettability gradients, sliding occurs without external forces since this gradient gives rise to an internal driving force. Here, we study via molecular dynamics simulations the more complex behavior when droplets are driven under the combined influence of an external and internal driving force. For comparison, the limiting cases of a single driving force are studied as well. During a large part of the sliding process over the borderline of both substrates, separating both wettabilities, the velocity is nearly constant. When expressing it as the product of the effective mobility and the effective force, the effective mobility mainly depends on the mobility of the initial substrate, experienced by the receding contact line. This observation can be reconciled with the properties of the flow pattern, indicating that the desorption of particles at the receding contact line is the time-limiting step. The effective force is the sum of the external force and a renormalized internal force. This renormalization can be interpreted as stronger dissipation effects when driving occurs via wettability gradients.
Analysis of entropy source for random number generation based on optical PUFs
Authors: Chen Kun , Wang Pidong , Huang Feng , Leng Xiao , Yao Yao
Published: May 2023

In this paper, we present an in-depth analysis for entropy source based on optical physical unclonable functions (PUFs). The randomness of speckle patterns is elaborated essentially according to its statistical characteristics. Various factors affecting the source of entropy have been analyzed in detail, including wavefront modulation, sensitivity, and universality of the optical PUF, and bit-depth settings of captured speckle patterns. In view of the above considerations, we demonstrate that the entropy source can achieve an ultra-high min-entropy (>0.985 bits/bit) while maintaining a high extraction rate of 75% and also verify its independent and identically distributed nature. These results provide an in-depth and comprehensive understanding of the developed entropy source and offer a firm foundation for its practical use.
Estimation of frequency factors for the calculation of kinetic isotope effects from classical and path integral free energy simulations
Authors: Giese Timothy J. , York Darrin M.
Published: May 2023

We use the modified Bigeleisen–Mayer equation to compute kinetic isotope effect values for non-enzymatic phosphoryl transfer reactions from classical and path integral molecular dynamics umbrella sampling. The modified form of the Bigeleisen–Mayer equation consists of a ratio of imaginary mode vibrational frequencies and a contribution arising from the isotopic substitution’s effect on the activation free energy, which can be computed from path integral simulation. In the present study, we describe a practical method for estimating the frequency ratio correction directly from umbrella sampling in a manner that does not require normal mode analysis of many geometry optimized structures. Instead, the method relates the frequency ratio to the change in the mass weighted coordinate representation of the minimum free energy path at the transition state induced by isotopic substitution. The method is applied to the calculation of 16/18O and 32/34S primary kinetic isotope effect values for six non-enzymatic phosphoryl transfer reactions. We demonstrate that the results are consistent with the analysis of geometry optimized transition state ensembles using the traditional Bigeleisen–Mayer equation. The method thus presents a new practical tool to enable facile calculation of kinetic isotope effect values for complex chemical reactions in the condensed phase.
Enhancing ammonia combustion with minimum hydrogen blended in presence of self-excited intermittent pulsating oscillations
Authors: Guan Yiheng , Zhao Dan
Published: May 2023

In this work, we propose and test a partial premixed fuel injection design of NH3−H2−O2 with double ring-shaped inlets to enhance ammonia combustion in an open-ended combustor by generating and sustaining pulsating combustion oscillations. Emphasis is being placed on determining the minimum amount of hydrogen being blended with ammonia in the presence of such self-excited pulsating oscillations. With the numerical model validated by comparing with experimental and theoretical data, we identify and systemically investigate three key thermodynamic parameters. They are shown to strongly affect the thermal, combustion, and emission performances. These parameters include the following: (1) total fuel mass flow rate ṁf; (2) mass fraction of hydrogen ω̇H2; and (3) the temperature TH of a heat exchanger implemented downstream of the combustor. It is interesting to observe that intermittent pulsating oscillations are sustained by such ammonia–hydrogen combustion. Furthermore, comparison is conducted between the present results and those with the classical single ring-shaped fuel inlet under the same flow and operating conditions. It is found that the exothermic heat of the proposed double-ring inlets is increased by 98.7% on average. The frequency of such intermittent oscillations is shown to increase with the decreased NH3 proportion. When pure hydrogen is supplied and passing through the outer ring inlet, the combustion limit can be greatly expanded, even if the inlet mass fraction of hydrogen is very small. The minimum hydrogen blended with ammonia is shown to be 0.1% to achieve a sustainable combustion and large-amplitude oscillations. The NO emission is found to be decreased, and H2O is shown to increase. The present study open ups an approach to enhance ammonia combustion by improving its flammability limit with the minimal hydrogen blended.
Sliding friction on ice
Authors: Miyashita N. , Yakini A. E. , Pyckhout-Hintzen W. , Persson B. N. J.
Published: May 2023

We study the friction when rectangular blocks made from rubber, polyethylene, and silica glass are sliding on ice surfaces at different temperatures ranging from −40 to 0 °C, and sliding speeds ranging from 3 μm/s to 1 cm s−1. We consider a winter tire rubber compound both in the form of a compact block and as a foam with ∼10% void volume. We find that both rubber compounds exhibit a similar friction on ice for all studied temperatures. As in a previous study at low temperatures and low sliding speeds, we propose that an important contribution to the friction force is due to slip between the ice surface and ice fragments attached to the rubber surface. At temperatures around 0 °C (or for high enough sliding speeds), a thin pre-melted water film will occur at the rubber–ice interface, and the contribution to the friction from shearing the area of real contact is small. In this case, the dominant contribution to the friction force is due to viscoelastic deformations of the rubber by the ice asperities. The sliding friction for polyethylene (PE) and silica glass (SG) blocks on ice differs strongly from that of rubber. The friction coefficient for PE is ∼0.04−0.15 and is relatively weakly velocity dependent except close to the ice melting temperature where the friction coefficient increases toward low sliding speeds. Silica glass exhibits a similarly low friction as PE for T > −10 °C but very large friction coefficients (of order unity) at low temperatures. For both PE and SG, unless the ice track is very smooth, the friction force depends on the position x along the sliding track. This is due to bumps on the ice surface, which are sheared off by the elastically stiff PE and SG blocks, resulting in a plowing-type of contribution to the friction force. This results in friction coefficients, which locally can be very large ∼1, and visual inspection of the ice surface after the sliding acts show ice wear particles (white powder) in regions where ice bumps occur. Similar effects can be expected for rubber blocks below the rubber glass transition temperature, and the rubber is in the (elastically stiff) glassy state.
All-optical logic gates using E-shaped silicon waveguides at 1.55 μm
Authors: Kotb Amer , Zoiros Kyriakos E. , Guo Chunlei
Published: May 2023

Owing to the advanced fabrication technology of silicon, silicon waveguides are particularly attractive for implementing all-optical signal processing devices and switches. Therefore, in this paper, a silicon-on-silica waveguide that consists of four slots arranged in the shape of letter E is proposed to be employed as the building block for simulating fundamental all-optical logic gates (AOLGs), including XOR, AND, OR, NOT, NOR, NAND, and XNOR, at 1.55 μm telecommunications wavelength. The operation concept of these logic gates relies on the constructive and destructive interference that results from the phase difference induced by optical beams that are incident on the E-shaped waveguide. The performance of the target logic gates is assessed against the contrast ratio (CR) metric. Moreover, the dependence of the spectral transmission on the device's key operating parameters is investigated and assessed. Compared to other reported designs, the results obtained by conducting simulations using the finite-difference-time-domain in lumerical commercial software show that the proposed waveguide can operate at a higher speed of 80 Gb/s and attain higher CRs of 36, 39, 35.5, 28.8, 30, 38, and 36.7 dB for logic XOR, AND, OR, NOT, NOR, NAND, and XNOR, respectively. This suggests that by using the proposed scheme, AOLGs could be realized more feasibly with greater performance and faster operation toward satisfying the present and future needs of light wave circuits and systems.
Experiment on terahertz metasurfaces of metal split ring resonators with bound state in the continuum
Authors: Zhang Tailin , Zhang Xingyuan , Shen Yun , Xu Yinsheng , Luo Laibin , Gu Jianqiang , Yang Sijia , Xu Jie , Deng Xiaohua
Published: May 2023

A bound state in the continuum (BIC) is a wave that coexists with a continuous wave but remains localized. In the terahertz band, BIC can design devices with an ultra-high mass factor (Q factor), which is of great value for terahertz science and technology, so we designed a terahertz BIC metasurface structure composed of metal split ring resonators (SRRs). According to the symmetric protection principle of superlattice mode, the leakage process of BIC states to the far field is studied by changing the gap width of SRR. By introducing multiple SRRs and changing their arrangement, we obtain three superlattice modes and BIC states. The leakage of BIC states into the far field is observed experimentally, which means that observable quasi-BIC patterns are formed. We verify a feasible method that allows for flexible design and implementation of BIC.
Recombination of vibrationally cold N2+ ions with electrons
Authors: Uvarova L. , Rednyk S. , Dohnal P. , Kassayová M. , Saito S. , Roučka Š. , Plašil R. , Johnsen R. , Glosík J.
Published: May 2023

Recombination of vibrationally cold N2+ ions with electrons was studied in the temperature range of 140–250 K. A cryogenic stationary afterglow apparatus equipped with cavity ring-down spectrometer and microwave diagnostics was utilized to probe in situ the time evolutions of number densities of particular rotational and vibrational states of N2+ ions and of electrons. The obtained value of the recombination rate coefficient for the recombination of the vibrational ground state of N2+ with electrons is αv=0 = (2.95 ± 0.50) × 10−7(300/T)(0.28±0.07) cm3 s−1, while that for the first vibrationally excited state was inferred as αv=1 = (4 ± 4) × 10−8 cm3 s−1 at 250 K.
On the superposition of solutions of the (3 + 1) dimensional Charney–Obukhov equation for the ocean
Authors: Kudryavtsev A. G. , Myagkov N. N.
Published: May 2023

New exact solutions describing Rossby waves and vortices in ocean propagating along the zonal direction at a constant velocity are found for the (3 + 1)-dimensional nonlinear Charney–Obukhov equation. These solutions are a partial superposition of previously discovered exact solutions of the Charney–Obukhov equation. Partial superposition is found for that part of the solution of the Charney–Obukhov equation, which complements the zonal stream. The presence of such a superposition in the solutions of a nonlinear equation with two nonlinear boundary conditions is a remarkable property of the Charney–Obukhov equation for the ocean and allows one to simulate a wide class of fluid flows based on exact solutions. As an example, we discuss solutions that include superposition of trigonometric functions and the functions of Bessel in a horizontal plane, and superposition of spherically symmetrical solutions in the vertical coordinate. Visualization of the solutions found shows that, depending on the values of the parameters included in the solutions, they can describe both a flow with a large number of vortices and a periodic structure with alternating high and low pressure fronts.
Hot-electron resonant terahertz bolometric detection in the graphene/black-AsP field-effect transistors with a floating gate
Authors: Ryzhii V. , Tang C. , Otsuji T. , Ryzhii M. , Mitin V. , Shur M. S.
Published: May 2023

We evaluate the terahertz (THz) detectors based on field-effect transistor (FET) with the graphene channel (GC) and a floating metal gate (MG) separated from the GC by a black-phosphorus (b-P) or black-arsenic (b-As) barrier layer. The operation of these GC-FETs is associated with the heating of the two-dimensional electron gas in the GC by impinging THz radiation leading to thermionic emission of the hot electrons from the GC to the MG. This results in the variation of the floating gate potential, which affects the source–drain current. At the THz radiation frequencies close to the plasmonic resonance frequencies in the gated GC, the variation of the source–drain current and, hence, the detector responsivity can be resonantly large.
Flow-induced rotation and wake characteristics of polygonal prisms subjected to laminar flow
Authors: Alam Md. Mahbub
Published: May 2023

This work presents numerical investigations of flow-induced rotation of three different polygonal prisms, including triangular, square, and pentagonal ones. Taking into account the torsional stiffness and damping, the rotation response is examined in a reduced velocity range of Ur = 3–15 at Re = 100. Four distinct oscillating regimes and associated vortex shedding modes are identified: 2S mode in the bifurcated-steady oscillating regime (3 ≤ Ur < 5 and 10 < Ur ≤ 15 for the triangular prism, 7 < Ur ≤ 11 for the square prism), 4S mode in the bifurcated-unsteady oscillating regime (12 ≤ Ur ≤ 15 for the square prism), 6S mode in the non-bifurcated oscillating regime (5 ≤ Ur ≤ 10 for the triangular prism), and 2S mode in the quasi-static regime (3 ≤ Ur < 8 for the square prism, the whole Ur range for the pentagonal prism). Moreover, the competitions between the pressure-induced torque and shear-induced torque vary in these four oscillating regimes. Specifically, the dominant component of the flow-induced torque is the pressure-induced torque in bifurcated-steady oscillating and bifurcated-unsteady oscillating regimes. By contrast, these two kinds of torques owning the nearly equal proportions possess the same and opposite sign in non-bifurcated oscillating and quasi-static regimes, respectively. The root-mean-squared rotary angle (θrms) depends on the cross-sectional shape and reduced velocity. The θrms of the triangular prism suddenly drops to the level of freely rotating case before two rising stages. The square prism starts to rotate violently when it enters the bifurcated-unsteady oscillating regime. For the pentagonal prism, a vortex-induced vibration-like rotation response is observed. Due to the different oscillating regimes, the general θrms of the triangular prism is the largest group, followed by the square prism and pentagonal prism in sequence.
A critical realist exploration of factors influencing engagement in diabetes prevention programs in rural settings
Authors: McMullen Britney , Duncanson Kerith , Schmidt David , Collins Clare , MacDonald-Wicks Lesley
Published: May 2023

Background Diabetes prevention programs are intended to reduce progression to type 2 diabetes, but are underutilised. This study aimed to explore people with prediabetes’ knowledge and attitudes about prediabetes, and their perceptions about engagement in preventive programs in a rural setting. The findings will inform strategies and recommendations to increase preventive health program engagement. Methods Using a qualitative approach with a critical realist methodology, semi-structured interviews were conducted with 20 rural participants with prediabetes from the Northern New South Wales Local Health District in 2021. Interviews were audio-recorded, transcribed verbatim and thematically analysed. The social-ecological model was used as a framework to interpret and action the study findings. Results Factors that empowered participants and facilitated a desire to engage in preventive programs included knowledge about prediabetes, a high level of social support, trusting and supportive relationships with health professionals, and a strong desire not to progress to diabetes. Barriers to program engagement included low health literacy levels, limited support, negative experiences with health services, and social and physical constraints. The factors that influenced engagement with preventive health programs were mapped to an individual, interpersonal, organisational, community and policy level, which highlighted the complex nature of behaviour change and the influence of underlying mechanisms. Conclusions Engagement in diabetes prevention programs was dependent on individual agency factors and structural barriers, each of which related to a level of the social-ecological model. Understanding the perceptions of people with prediabetes will inform strategies to overcome multi-level barriers to preventive health program engagement in rural settings.
Developmental bias predicts 60 million years of wing shape evolution
Authors: Rohner Patrick T. , Berger David
Published: May 2023

The degree to which developmental biases affect trait evolution is subject to much debate. Here, we first quantify fluctuating asymmetry as a measure of developmental variability, i.e., the propensity of developmental systems to create some phenotypic variants more often than others, and show that it predicts phenotypic and standing genetic variation as well as deep macroevolutionary divergence in wing shape in sepsid flies. Comparing our data to the findings of a previous study demonstrates that developmental variability in the sepsid fly
Sepsis punctum
strongly aligns with mutational, standing genetic, and macroevolutionary variation in the Drosophilidae––a group that diverged from the sepsid lineage ca. 64 My ago. We also find that developmental bias in
S. punctum
wing shape aligns with the effects of allometry, but less so with putatively adaptive thermal plasticity and population differentiation along latitude. Our findings demonstrate that developmental bias in fly wings predicts evolvability and macroevolutionary trajectories on a much greater scale than previously appreciated but also suggest that causal explanations for such alignments may go beyond simple constraint hypotheses.
CRISPR editing demonstrates rs10490924 raised oxidative stress in iPSC-derived retinal cells from patients with
ARMS2/HTRA1
-related AMD
Authors: Chang Ya-Ju , Jenny Laura A. , Li Yong-Shi , Cui Xuan , Kong Yang , Li Yao , Sparrow Janet R. , Tsang Stephen H.
Published: May 2023

Genome-wide association studies (GWAS) have identified genetic risk loci for age-related macular degeneration (AMD) on the chromosome 10q26 (Chr10) locus and are tightly linked: the A69S (G>T) rs10490924 single-nucleotide variant (SNV) and the AATAA-rich insertion–deletion (indel, del443/ins54), which are found in the age-related maculopathy susceptibility 2 (
ARMS2
) gene, and the G512A (G>A) rs11200638 SNV, which is found in the high-temperature requirement A serine peptidase 1 (
HTRA1
) promoter. The fourth variant is Y402H complement factor H (
CFH
), which directs
CFH
 signaling. CRISPR manipulation of retinal pigment epithelium (RPE) cells may allow one to isolate the effects of the individual SNV and thus identify SNV-specific effects on cell phenotype. Clustered regularly interspaced short palindromic repeats (CRISPR) editing demonstrates that rs10490924 raised oxidative stress in induced pluripotent stem cell (iPSC)-derived retinal cells from patients with AMD. Sodium phenylbutyrate preferentially reverses the cell death caused by
ARMS2
rs10490924 but not
HTRA1
rs11200638. This study serves as a proof of concept for the use of patient-specific iPSCs for functional annotation of tightly linked GWAS to study the etiology of a late-onset disease phenotype. More importantly, we demonstrate that antioxidant administration may be useful for reducing reactive oxidative stress in AMD, a prevalent late-onset neurodegenerative disorder.
Dual regulations of cell cycle regulator DPa by auxin in
Arabidopsis
root distal stem cell maintenance
Authors: Wang Junxia , Li Xiaoxuan , Chen Xiaolu , Tang Wenxin , Yu Zipeng , Xu Tongda , Tian Huiyu , Ding Zhaojun
Published: May 2023

The plant hormone auxin plays a key role to maintain root stem cell identity which is essential for root development. However, the molecular mechanism by which auxin regulates root distal stem cell (DSC) identity is not well understood. In this study, we revealed that the cell cycle factor DPa is a vital regulator in the maintenance of root DSC identity through multiple auxin signaling cascades. On the one hand, auxin positively regulates the transcription of
DPa
via AUXIN RESPONSE FACTOR 7 and ARF19. On the other hand, auxin enhances the protein stability of DPa through MITOGEN-ACTIVATED PROTEIN KINASE 3 (MPK3)/MPK6-mediated phosphorylation. Consistently, mutation of the identified three threonine residues (Thr
10
, Thr
25
, and Thr
227
) of DPa to nonphosphorylated form alanine (DPa
3A
) highly decreased the phosphorylation level of DPa, which decreased its protein stability and affected the maintenance of root DSC identity. Taken together, this study provides insight into the molecular mechanism of how auxin regulates root distal stem cell identity through the dual regulations of DPa at both transcriptional and posttranslational levels.
Nanotopography modulates intracellular excitable systems through cytoskeleton actuation
Authors: Yang Qixin , Miao Yuchuan , Banerjee Parijat , Hourwitz Matt J. , Hu Minxi , Qing Quan , Iglesias Pablo A. , Fourkas John T. , Losert Wolfgang , Devreotes Peter N.
Published: May 2023

Cellular sensing of most environmental cues involves receptors that affect a signal-transduction excitable network (STEN), which is coupled to a cytoskeletal excitable network (CEN). We show that the mechanism of sensing of nanoridges is fundamentally different. CEN activity occurs preferentially on nanoridges, whereas STEN activity is constrained between nanoridges. In the absence of STEN, waves disappear, but long-lasting F-actin puncta persist along the ridges. When CEN is suppressed, wave propagation is no longer constrained by nanoridges. A computational model reproduces these experimental observations. Our findings indicate that nanotopography is sensed directly by CEN, whereas STEN is only indirectly affected due to a CEN-STEN feedback loop. These results explain why texture sensing is robust and acts cooperatively with multiple other guidance cues in complex, in vivo microenvironments.
MICU1 occludes the mitochondrial calcium uniporter in divalent-free conditions
Authors: Rodríguez-Prados Macarena , Berezhnaya Elena , Castromonte Maria Teresa , Menezes-Filho Sergio L. , Paillard Melanie , Hajnóczky György
Published: May 2023

Mitochondrial Ca
2+
 uptake is mediated by the mitochondrial uniporter complex (mtCU) that includes a tetramer of the pore-forming subunit, MCU, a scaffold protein, EMRE, and the EF-hand regulatory subunit, MICU1 either homodimerized or heterodimerized with MICU2/3. MICU1 has been proposed to regulate Ca
2+
uptake via the mtCU by physically occluding the pore and preventing Ca
2+
flux at resting cytoplasmic [Ca
2+
] (free calcium concentration) and to increase Ca
2+
flux at high [Ca
2+
] due to cooperative activation of MICUs EF-hands. However, mtCU and MICU1 functioning when its EF-hands are unoccupied by Ca
2+
is poorly studied due to technical limitations. To overcome this barrier, we have studied the mtCU in divalent-free conditions by assessing the Ru265-sensitive Na
+
 influx using fluorescence-based measurement of mitochondrial matrix [Na
+
] (free sodium concentration) rise and the ensuing depolarization and swelling. We show an increase in all these measures of Na
+
uptake in MICU1KO cells as compared to wild-type (WT) and rescued MICU1KO HEK cells. However, mitochondria in WT cells and MICU1 stable-rescued cells still allowed some Ru265-sensitive Na
+
influx that was prevented by MICU1 in excess upon acute overexpression. Thus, MICU1 restricts the cation flux across the mtCU in the absence of Ca
2+
, but even in cells with high endogenous MICU1 expression such as HEK, some mtCU seem to lack MICU1-dependent gating. We also show rearrangement of the mtCU and altered number of functional channels in MICU1KO and different rescues, and loss of MICU1 during mitoplast preparation, that together might have obscured the pore-blocking function of MICU1 in divalent-free conditions in previous studies.
Evolution and diversification of the ACT-like domain associated with plant basic helix–loop–helix transcription factors
Authors: Lee Yun Sun , Shiu Shin-Han , Grotewold Erich
Published: May 2023

Basic helix–loop–helix (bHLH) proteins are one of the largest families of transcription factor (TF) in eukaryotes, and ~30% of all flowering plants’ bHLH TFs contain the aspartate kinase, chorismate mutase, and TyrA (ACT)-like domain at variable distances C-terminal from the bHLH. However, the evolutionary history and functional consequences of the bHLH/ACT-like domain association remain unknown. Here, we show that this domain association is unique to the plantae kingdom with green algae (chlorophytes) harboring a small number of bHLH genes with variable frequency of ACT-like domain’s presence. bHLH-associated ACT-like domains form a monophyletic group, indicating a common origin. Indeed, phylogenetic analysis results suggest that the association of ACT-like and bHLH domains occurred early in Plantae by recruitment of an ACT-like domain in a common ancestor with widely distributed
ACT DOMAIN REPEAT
(
ACR
) genes by an ancestral bHLH gene. We determined the functional significance of this association by showing that
Chlamydomonas reinhardtii
ACT-like domains mediate homodimer formation and negatively affect DNA binding of the associated bHLH domains. We show that, while ACT-like domains have experienced faster selection than the associated bHLH domain, their rates of evolution are strongly and positively correlated, suggesting that the evolution of the ACT-like domains was constrained by the bHLH domains. This study proposes an evolutionary trajectory for the association of ACT-like and bHLH domains with the experimental characterization of the functional consequence in the regulation of plant-specific processes, highlighting the impacts of functional domain coevolution.
Nonpathological inflammation drives the development of an avian flight adaptation
Authors: Rashid Dana J. , Sheheen Joseph R. , Huey Tori , Surya Kevin , Sanders Jackson B. , Horner John R. , Voyich Jovanka , Chapman Susan C.
Published: May 2023

The development of modern birds provides a window into the biology of their dinosaur ancestors. We investigated avian postnatal development and found that sterile inflammation drives formation of the pygostyle, a compound structure resulting from bone fusion in the tail. Inflammation is generally induced by compromised tissue integrity, but here is involved in normal bone development. Transcriptome profiling and immuno/histochemistry reveal a robust inflammatory response that resembles bone fracture healing. The data suggest the involvement of necroptosis and multiple immune cell types, notably heterophils (the avian equivalent of neutrophils). Additionally, nucleus pulposus structures, heretofore unknown in birds, are involved in disc remodeling. Anti-inflammatory corticosteroid treatment inhibited vertebral fusion, substantiating the crucial role of inflammation in the ankylosis process. This study shows that inflammation can drive developmental skeletogenesis, in this case leading to the formation of a flight-adapted tail structure on the evolutionary path to modern avians.
PGE
2
alters chromatin through H2A.Z-variant enhancer nucleosome modification to promote hematopoietic stem cell fate
Authors: Sporrij Audrey , Choudhuri Avik , Prasad Meera , Muhire Brejnev , Fast Eva M. , Manning Margot E. , Weiss Jodi D. , Koh Michelle , Yang Song , Kingston Robert E. , Tolstorukov Michael Y. , Clevers Hans , Zon Leonard I.
Published: May 2023

Prostaglandin E2 (PGE
2
) and 16,16-dimethyl-PGE
2
(dmPGE
2
) are important regulators of hematopoietic stem and progenitor cell (HSPC) fate and offer potential to enhance stem cell therapies [C. Cutler
et al.
Blood
122
, 3074–3081(2013); W. Goessling
et al.
Cell Stem Cell
8
, 445–458 (2011); W. Goessling
et al.
Cell
136
, 1136–1147 (2009)]. Here, we report that PGE
2
-induced changes in chromatin at enhancer regions through histone-variant H2A.Z permit acute inflammatory gene induction to promote HSPC fate. We found that dmPGE
2
-inducible enhancers retain MNase-accessible, H2A.Z-variant nucleosomes permissive of CREB transcription factor (TF) binding. CREB binding to enhancer nucleosomes following dmPGE
2
stimulation is concomitant with deposition of histone acetyltransferases p300 and Tip60 on chromatin. Subsequent H2A.Z acetylation improves chromatin accessibility at stimuli-responsive enhancers. Our findings support a model where histone-variant nucleosomes retained within inducible enhancers facilitate TF binding. Histone-variant acetylation by TF-associated nucleosome remodelers creates the accessible nucleosome landscape required for immediate enhancer activation and gene induction. Our work provides a mechanism through which inflammatory mediators, such as dmPGE
2
, lead to acute transcriptional changes and modify HSPC behavior to improve stem cell transplantation.
Epigenetic silencing of selected hypothalamic neuropeptides in narcolepsy with cataplexy
Authors: Seifinejad Ali , Ramosaj Mergim , Shan Ling , Li Sha , Possovre Marie-Laure , Pfister Corinne , Fronczek Rolf , Garrett-Sinha Lee A. , Frieser David , Honda Makoto , Arribat Yoan , Grepper Dogan , Amati Francesca , Picot Marie , Agnoletto Andrea , Iseli Christian , Chartrel Nicolas , Liblau Roland , Lammers Gert J. , Vassalli Anne , Tafti Mehdi
Published: May 2023

Narcolepsy with cataplexy is a sleep disorder caused by deficiency in the hypothalamic neuropeptide hypocretin/orexin (HCRT), unanimously believed to result from autoimmune destruction of hypocretin-producing neurons. HCRT deficiency can also occur in secondary forms of narcolepsy and be only temporary, suggesting it can occur without irreversible neuronal loss. The recent discovery that narcolepsy patients also show loss of hypothalamic (corticotropin-releasing hormone) CRH-producing neurons suggests that other mechanisms than cell-specific autoimmune attack, are involved. Here, we identify the HCRT cell-colocalized neuropeptide QRFP as the best marker of HCRT neurons. We show that if HCRT neurons are ablated in mice, in addition to 
Hcrt,
Qrfp
transcript is also lost in the lateral hypothalamus, while in mice where only the 
Hcrt
 gene is inactivated
Qrfp
is unchanged. Similarly, postmortem hypothalamic tissues of narcolepsy patients show preserved 
QRFP
 expression, suggesting the neurons are present but fail to actively produce HCRT. We show that the promoter of the 
HCRT
 gene of patients exhibits hypermethylation at a methylation-sensitive and evolutionary-conserved PAX5:ETS1 transcription factor-binding site, suggesting the gene is subject to transcriptional silencing. We show also that in addition to HCRT, 
CRH
 and Dynorphin (
PDYN
) gene promoters, exhibit hypermethylation in the hypothalamus of patients. Altogether, we propose that
HCRT
, 
PDYN
, and 
CRH
are epigenetically silenced by a hypothalamic assault (inflammation) in narcolepsy patients, without concurrent cell death. Since methylation is reversible, our findings open the prospect of reversing or curing narcolepsy.
Stress resilience-enhancing drugs preserve tissue structure and function in degenerating retina via phosphodiesterase inhibition
Authors: Luu Jennings C. , Saadane Aicha , Leinonen Henri , Choi Elliot H. , Gao Fangyuan , Lewandowski Dominik , Halabi Maximilian , Sander Christopher L. , Wu Arum , Wang Jacob M. , Singh Rupesh , Gao Songqi , Lessieur Emma M. , Dong Zhiqian , Palczewska Grazyna , Mullins Robert F. , Peachey Neal S. , Kiser Philip D. , Tabaka Marcin , Kern Timothy S. , Palczewski Krzysztof
Published: May 2023

Chronic, progressive retinal diseases, such as age-related macular degeneration (AMD), diabetic retinopathy, and retinitis pigmentosa, arise from genetic and environmental perturbations of cellular and tissue homeostasis. These disruptions accumulate with repeated exposures to stress over time, leading to progressive visual impairment and, in many cases, legal blindness. Despite decades of research, therapeutic options for the millions of patients suffering from these disorders remain severely limited, especially for treating earlier stages of pathogenesis when the opportunity to preserve the retinal structure and visual function is greatest. To address this urgent, unmet medical need, we employed a systems pharmacology platform for therapeutic development. Through integrative single-cell transcriptomics, proteomics, and phosphoproteomics, we identified universal molecular mechanisms across distinct models of age-related and inherited retinal degenerations, characterized by impaired physiological resilience to stress. Here, we report that selective, targeted pharmacological inhibition of cyclic nucleotide phosphodiesterases (PDEs), which serve as critical regulatory nodes that modulate intracellular second messenger signaling pathways, stabilized the transcriptome, proteome, and phosphoproteome through downstream activation of protective mechanisms coupled with synergistic inhibition of degenerative processes. This therapeutic intervention enhanced resilience to acute and chronic forms of stress in the degenerating retina, thus preserving tissue structure and function across various models of age-related and inherited retinal disease. Taken together, these findings exemplify a systems pharmacology approach to drug discovery and development, revealing a new class of therapeutics with potential clinical utility in the treatment or prevention of the most common causes of blindness.
High sensitivity top–down proteomics captures single muscle cell heterogeneity in large proteoforms
Authors: Melby Jake A. , Brown Kyle A. , Gregorich Zachery R. , Roberts David S. , Chapman Emily A. , Ehlers Lauren E. , Gao Zhan , Larson Eli J. , Jin Yutong , Lopez Justin R. , Hartung Jared , Zhu Yanlong , McIlwain Sean J. , Wang Daojing , Guo Wei , Diffee Gary M. , Ge Ying
Published: May 2023

Single-cell proteomics has emerged as a powerful method to characterize cellular phenotypic heterogeneity and the cell-specific functional networks underlying biological processes. However, significant challenges remain in single-cell proteomics for the analysis of proteoforms arising from genetic mutations, alternative splicing, and post-translational modifications. Herein, we have developed a highly sensitive functionally integrated top–down proteomics method for the comprehensive analysis of proteoforms from single cells. We applied this method to single muscle fibers (SMFs) to resolve their heterogeneous functional and proteomic properties at the single-cell level. Notably, we have detected single-cell heterogeneity in large proteoforms (>200 kDa) from the SMFs. Using SMFs obtained from three functionally distinct muscles, we found fiber-to-fiber heterogeneity among the sarcomeric proteoforms which can be related to the functional heterogeneity. Importantly, we detected multiple isoforms of myosin heavy chain (~223 kDa), a motor protein that drives muscle contraction, with high reproducibility to enable the classification of individual fiber types. This study reveals single muscle cell heterogeneity in large proteoforms and establishes a direct relationship between sarcomeric proteoforms and muscle fiber types, highlighting the potential of top–down proteomics for uncovering the molecular underpinnings of cell-to-cell variation in complex systems.
Direct tests of cytochrome
c
and
c
1
functions in the electron transport chain of malaria parasites
Authors: Espino-Sanchez Tanya J. , Wienkers Henry , Marvin Rebecca G. , Nalder Shai-anne , García-Guerrero Aldo E. , VanNatta Peter E. , Jami-Alahmadi Yasaman , Mixon Blackwell Amanda , Whitby Frank G. , Wohlschlegel James A. , Kieber-Emmons Matthew T. , Hill Christopher P. , A. Sigala Paul
Published: May 2023

The mitochondrial electron transport chain (ETC) of
Plasmodium
malaria parasites is a major antimalarial drug target, but critical cytochrome (cyt) functions remain unstudied and enigmatic. Parasites express two distinct cyt
c
homologs (
c
and
c
-2) with unusually sparse sequence identity and uncertain fitness contributions.
P. falciparum
cyt
c
-2 is the most divergent eukaryotic cyt
c
homolog currently known and has sequence features predicted to be incompatible with canonical ETC function. We tagged both cyt
c
homologs and the related cyt
c
1
for inducible knockdown. Translational repression of cyt
c
and cyt
c
1
was lethal to parasites, which died from ETC dysfunction and impaired ubiquinone recycling. In contrast, cyt
c
-2 knockdown or knockout had little impact on blood-stage growth, indicating that parasites rely fully on the more conserved cyt
c
for ETC function. Biochemical and structural studies revealed that both cyt
c
and
c
-2 are hemylated by holocytochrome
c
synthase, but UV-vis absorbance and EPR spectra strongly suggest that cyt
c
-2 has an unusually open active site in which heme is stably coordinated by only a single axial amino acid ligand and can bind exogenous small molecules. These studies provide a direct dissection of cytochrome functions in the ETC of malaria parasites and identify a highly divergent
Plasmodium
cytochrome
c
with molecular adaptations that defy a conserved role in eukaryotic evolution.
Intestinal bile acids provide a surmountable barrier against
C. difficile
TcdB-induced disease pathogenesis
Authors: Icho Simoun , Ward Jennifer S. , Tam John , Kociolek Larry K. , Theriot Casey M. , Melnyk Roman A.
Published: May 2023

Intestinal bile acids play an essential role in the
Clostridioides difficile
lifecycle having been shown in vitro to modulate various aspects of pathogenesis, including spore germination, vegetative growth, and more recently the action of the primary virulence determinant, TcdB. Here, we investigated whether physiological levels of the total pool of intestinal bile acids in mice and humans protect against TcdB action. Small molecules extracted from the lumenal contents of the small intestine, cecum, colon, and feces were found to inhibit TcdB in accordance with the differential amounts of total bile acids in each compartment. Extracts from antibiotic-treated and germ-free mice, despite harboring dramatically altered bile acid profiles, unexpectedly also prevented TcdB-induced cell rounding to similar extents. We show that protection, however, is surmountable and can be overcome at higher doses of TcdB—typical to those seen during severe
C. difficile
infection—suggesting that the protective properties of intestinal bile acids are operant primarily under low to moderate toxin levels. Taken together, these findings demonstrate a role for intestinal bile acids in attenuating virulence, provide insights into asymptomatic carriage of toxigenic
C. difficile
, and inform strategies to manipulate bile acid levels for therapeutic benefit.
Basal cell carcinoma - new aspects of diagnosis and treatment
Authors: Wennberg Ann-Marie
Published: May 2023

This article does not have an abstract.
The Clinical Spectrum of Congenital Ichthyosis in Sweden: A Review of 127 Cases
Authors: Vahlquist A , Gånemo A , Pigg M , Virtanen M , Westermark P
Published: May 2023

Congenital ichthyosis comprises a rare group of usually
monogenetic diseases that present at birth as a collodion
phenotype or as variable degrees of ichthyosiform
erythroderma, with or without superficial blisters. Depending
on which gene mutation causes the disease, the
skin problems later in life may range from a severe
lamellar or bullous ichthyosis to mild or only focally
expressed hyperkeratotic lesions. It is obviously important,
but sometimes painstakingly difficult, to make a
correct diagnosis already in infancy. Fortunately, recent
advances in our understanding of the molecular
genetics of ichthyosis have led to several new diagnostic
tools that are continuously being updated. Based on
this development, and on our own 5 years of experience
in a national genodermatosis centre, we describe
127 cases of congenital ichthyosis examined in childhood
or adulthood. Applying a combination of phenotypic
and genotypic criteria, the patients were classified
into three main groups: 1) Bullous ichthyosis
(epidermolytic hyperkeratosis) and related disorders
due to keratin mutations (n=21); 2) Non-bullous ichthyosiform
erythroderma and lamellar ichthyosis
mainly due to transglutaminase 1 mutations (n=80); 3)
Syndromic ichthyosis, i.e. systemic (multi-organ) diseases
due to many different causes (n=26). Each group
could be further stratified into 4‚Äì11 entities using mutation
analysis, electron microscopy of epidermis and
various other techniques. Our findings are discussed
in relation to recent data in the literature emphasizing
the clinical usefulness of various diagnostic procedures
for ichthyosis.
AAFL: automatic association feature learning for gene signature identification of cancer subtypes in single-cell RNA-seq data
Authors: Huang Meng , Long Changzhou , Ma Jiangtao
Published: May 2023

Single-cell RNA-sequencing (scRNA-seq) technologies have enabled the study of human cancers in individual cells, which explores the cellular heterogeneity and the genotypic status of tumors. Gene signature identification plays an important role in the precise classification of cancer subtypes. However, most existing gene selection methods only select the same informative genes for each subtype. In this study, we propose a novel gene selection method, automatic association feature learning (AAFL), which automatically identifies different gene signatures for different cell subpopulations (cancer subtypes) at the same time. The proposed AAFL method combines the residual network with the low-rank network, which selects genes that are most associated with the corresponding cell subpopulations. Moreover, the differential expression genes are acquired before gene selection to filter the redundant genes. We apply the proposed feature learning method to the real cancer scRNA-seq data sets (melanoma) to identify cancer subtypes and detect gene signatures of identified cancer subtypes. The experimental results demonstrate that the proposed method can automatically identify different gene signatures for identified cancer subtypes. Gene ontology enrichment analysis shows that the identified gene signatures of different subtypes reveal the key biological processes and pathways. These gene signatures are expected to bring important implications for understanding cellular heterogeneity and the complex ecosystem of tumors.
SSNMDI: a novel joint learning model of semi-supervised non-negative matrix factorization and data imputation for clustering of single-cell RNA-seq data
Authors: Qiu Yushan , Yan Chang , Zhao Pu , Zou Quan
Published: May 2023

Motivation

Single-cell RNA sequencing (scRNA-seq) technology attracts extensive attention in the biomedical field. It can be used to measure gene expression and analyze the transcriptome at the single-cell level, enabling the identification of cell types based on unsupervised clustering. Data imputation and dimension reduction are conducted before clustering because scRNA-seq has a high ‘dropout’ rate, noise and linear inseparability. However, independence of dimension reduction, imputation and clustering cannot fully characterize the pattern of the scRNA-seq data, resulting in poor clustering performance. Herein, we propose a novel and accurate algorithm, SSNMDI, that utilizes a joint learning approach to simultaneously perform imputation, dimensionality reduction and cell clustering in a non-negative matrix factorization (NMF) framework. In addition, we integrate the cell annotation as prior information, then transform the joint learning into a semi-supervised NMF model. Through experiments on 14 datasets, we demonstrate that SSNMDI has a faster convergence speed, better dimensionality reduction performance and a more accurate cell clustering performance than previous methods, providing an accurate and robust strategy for analyzing scRNA-seq data. Biological analysis are also conducted to validate the biological significance of our method, including pseudotime analysis, gene ontology and survival analysis. We believe that we are among the first to introduce imputation, partial label information, dimension reduction and clustering to the single-cell field.

Availability and implementation

The source code for SSNMDI is available at https://github.com/yushanqiu/SSNMDI.
Navigating Available Treatment Options for Carbapenem-ResistantAcinetobacter baumannii-calcoaceticusComplex Infections
Authors: Shields Ryan K , Paterson David L , Tamma Pranita D
Published: May 2023

Carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex (CRAB) is one of the top-priority pathogens for new antibiotic development. Unlike other antibiotic-resistant threats, none of the available therapies have been shown to consistently reduce mortality or improve patient outcomes in clinical trials. Antibiotic combination therapy is routinely used in clinical practice; however, the preferred combination has not been defined. This narrative review focuses on evidence-based solutions for the treatment of invasive CRAB infections. We dissect the promise and perils of traditional agents used in combination, such as colistin, sulbactam, and the tetracyclines, and offer clinical pearls based on our interpretation of the available data. Next, we investigate the merits of newly developed β-lactam agents like cefiderocol and sulbactam-durlobactam, which have demonstrated contrasting results in recent randomized clinical trials. The review concludes with the authors’ perspective on the evolving treatment landscape for CRAB infections, which is complicated by limited clinical data, imperfect treatment options, and a need for future clinical trials. We propose that effective treatment for CRAB infections requires a personalized approach that incorporates host factors, the site of infection, pharmacokinetic-pharmacodynamic principles, local molecular epidemiology of CRAB isolates, and careful interpretation of antibiotic susceptibility testing results. In most clinical scenarios, a dose-optimized, sulbactam-based regimen is recommended with the addition of at least one other in vitro active agent. Should sulbactam-durlobactam receive regulatory approval, recommendations will need to be re-evaluated with the most recent evidence.