BACKGROUND & AIMS: :We studied the involvement of deep cortical layer neurons in processing callosal information in the rat. We observed with electron microscopy that both parvalbumin (PV)-labeled profiles and unlabeled dendritic spines of deep cortical layer neurons receive synapses from the contralateral hemisphere. Stimulation of callosal fibers elicited monosynaptic excitatory postsynaptic currents in both layer VI pyramidal neurons and gamma-aminobutyric acidergic (GABAergic) interneurons immunopositive for the vesicular GABA transporter and PV. Pyramidal cells had intrinsic electrophysiological properties and synaptic responses with slow kinetics and a robust N-metyhl-D-aspartate (NMDA) component. In contrast, GABAergic interneurons had intrinsic membrane properties and synaptic responses with faster kinetics and a less pronounced NMDA component. Consistent with these results, the temporal integration of callosal input was effective over a significantly longer time window in pyramidal neurons compared with GABAergic interneurons. Interestingly, callosal stimulation did not evoke feedforward inhibition in all GABAergic interneurons and in the majority of pyramidal neurons tested. Furthermore, retrogradely labeled layer VI pyramidal neurons of the contralateral cortex responded monosynaptically to callosal stimulation, suggesting interconnectivity between callosally projecting neurons. The data show that pyramidal neurons and GABAergic interneurons of deep cortical layers receive interhemispheric information directly and have properties supporting their distinct roles.

背景与目标： : 我们研究了深皮质层神经元在处理大鼠call骨信息中的参与。我们用电子显微镜观察到，浅白蛋白 (PV) 标记的轮廓和深皮质层神经元的未标记的树突棘均从对侧半球接收突触。Call骨纤维的刺激在VI层锥体神经元和 γ-氨基丁酸 (GABA能) 中间神经元中均引起单突触兴奋性突触后电流，对囊泡GABA转运蛋白和PV免疫呈阳性。锥体细胞具有内在的电生理特性和突触反应，动力学缓慢，并且具有强大的N-metyhl-D-天冬氨酸 (NMDA) 成分。相反，gaba能中间神经元具有内在的膜特性和突触反应，其动力学更快，NMDA成分不那么明显。与这些结果一致，与gaba能中间神经元相比，在锥体神经元中，call骨输入的时间整合在明显更长的时间窗口内有效。有趣的是，在所有gaba能中间神经元和大多数测试的锥体神经元中，call刺激并未引起前馈抑制。此外，对侧皮层的逆行标记的第VI层锥体神经元对call骨刺激单突触反应，表明call骨投射神经元之间的相互连接。数据表明，皮层深层的锥体神经元和gaba能中间神经元直接接收半球间信息，并具有支持其独特作用的特性。

BACKGROUND & AIMS: :Succinylation is a type of protein post-translational modification (PTM), which can play important roles in a variety of cellular processes. Due to an increasing number of site-specific succinylated peptides obtained from high-throughput mass spectrometry (MS), various tools have been developed for computationally identifying succinylated sites on proteins. However, most of these tools predict succinylation sites based on traditional machine learning methods. Hence, this work aimed to carry out the succinylation site prediction based on a deep learning model. The abundance of MS-verified succinylated peptides enabled the investigation of substrate site specificity of succinylation sites through sequence-based attributes, such as position-specific amino acid composition, the composition of k-spaced amino acid pairs (CKSAAP), and position-specific scoring matrix (PSSM). Additionally, the maximal dependence decomposition (MDD) was adopted to detect the substrate signatures of lysine succinylation sites by dividing all succinylated sequences into several groups with conserved substrate motifs. According to the results of ten-fold cross-validation, the deep learning model trained using PSSM and informative CKSAAP attributes can reach the best predictive performance and also perform better than traditional machine-learning methods. Moreover, an independent testing dataset that truly did not exist in the training dataset was used to compare the proposed method with six existing prediction tools. The testing dataset comprised of 218 positive and 2621 negative instances, and the proposed model could yield a promising performance with 84.40% sensitivity, 86.99% specificity, 86.79% accuracy, and an MCC value of 0.489. Finally, the proposed method has been implemented as a web-based prediction tool (CNN-SuccSite), which is now freely accessible at http://csb.cse.yzu.edu.tw/CNN-SuccSite/ .

背景与目标： : 琥珀酰化是蛋白质翻译后修饰 (PTM) 的一种，可以在多种细胞过程中发挥重要作用。由于从高通量质谱 (MS) 获得的位点特异性琥珀酰化肽的数量不断增加，因此已开发出各种工具来计算识别蛋白质上的琥珀酰化位点。但是，大多数这些工具都基于传统的机器学习方法来预测琥珀酰化位点。因此，这项工作旨在基于深度学习模型进行琥珀酰化位点预测。MS验证的琥珀酰化肽的丰度使得能够通过基于序列的属性 (例如位置特异性氨基酸组成，k间隔氨基酸对 (CKSAAP) 的组成和位置特异性评分矩阵 (PSSM)) 研究琥珀酰化位点的底物位点特异性。此外，通过将所有琥珀酰化序列分为几个具有保守的底物基序的组，采用最大依赖性分解 (MDD) 来检测赖氨酸琥珀酰化位点的底物特征。根据十倍交叉验证的结果，使用PSSM和信息性CKSAAP属性训练的深度学习模型可以达到最佳的预测性能，并且性能也优于传统的机器学习方法。此外，使用训练数据集中真正不存在的独立测试数据集将所提出的方法与六种现有的预测工具进行比较。测试数据集由218阳性和2621阴性实例组成，所提出的模型可以产生具有84.40% 灵敏度、86.99% 特异性、86.79% 准确性和0.489 MCC值的有希望的性能。最后，所提出的方法已实现为基于web的预测工具 (cnn-succsite)，现在可以在http://csb.cse.yzu.edu.tw/cnn-succsite/上自由访问。

BACKGROUND & AIMS: AIM/BACKGROUND:Treatment of DVT with LMWHs has been shown recently to be as effective as UFH with suggested lower costs. This study was conducted to determine and compare the cost of in-patient hospital treatment versus outpatient hospital treatment of patients with DVT. METHOD:All adult patients with acute proximal DVT referred to the Emergency Department of King Khalid University Hospital, Riyadh, Saudi Arabia between August 2009 and August 2010 were invited to the study. An economic analysis was performed to compare the cost impact of outpatients versus hospital treatment. RESULTS:Sixty-one patients were included in the study, 31 were followed in the outpatient setting and 30 as the control group (inpatients). There were no significant differences in the outcome between the outpatient and inpatient group; three patients (9.7%) in the outpatient group and four patients (13.3%) in the inpatient group had recurrent DVT. Mean nursing cost was $55 for the outpatient group and $215 for the inpatient group, mean laboratory monitoring cost was $638 for outpatient group and $1511 for the inpatient group. Hospital stay and doctor's fees amounted to a mean of $1000 for outpatient treatment and $2387 for inpatient treatment, p < 0.0001. The mean outpatient cost was significantly lower than the inpatient cost ($1750 vs. $4338, p < 0.0001). CONCLUSION:Outpatient treatment of patients with DVT using LMWHs is cost-effective with no significant differences in the outcome of patients. OPD treatment of DVT is feasible in Saudi Arabia provided there is enough logistic support from thrombosis clinics and those involved in DVT care.

背景与目标：

BACKGROUND & AIMS: Background:Ingrowth-core method is a useful tool to determine fine root growth of standing crops by inserting root-free soil in mesh-bags for certain period of time. However, the root density observed by the method does not directly explain the nutrient uptake potential of crop plants as it varies over soil depth and incubation time. We have inserted an access-tube up to 4.2 m of soil depth with openings directly under crop plants, through which ingrowth-cores containing labelled soil with nutrient tracers were installed, called core-labelling technique (CLT). The main advantage of CLT would be its capacity to determine both root density and root activity from the same crop plants in deep soil layers. We tested the validity of the new method using a model crop species, alfalfa (Medicago sativa) against three depth-levels (1.0, 2.5 and 4.2 m), three sampling spots with varying distance (0-0.36, 0.36-0.72 and > 5 m from core-labelled spot), two sampling times (week 4 and 8), and two plant parts (young and old leaves) under two field experiments (spring and autumn). Results:Using CLT, we were able to observe both deep root growth and root activity up to 4.2 m of soil depth. Tracer concentrations revealed that there was no sign of tracer-leakage to adjacent areas which is considered to be advantageous over the generic tracer-injection. Root activity increased with longer incubation period and tracer concentrations were higher in younger leaves only for anionic tracers. Conclusions:Our results indicate that CLT can lead to a comprehensive deep root study aiming at measuring both deep root growth and root activity from the same plants. Once produced and installed, the access-tubes and ingrowth-cores can be used for a long-term period, which reduces the workload and cost for the research. Therefore, CLT has a wide range of potential applications to the research involving roots in deep soil layers, which requires further confirmation by future experiments.

背景与目标：

BACKGROUND & AIMS: :The electrophysiological properties of 87 neurons in the deep dorsal horn (laminae III-VI) of the rat spinal cord have been investigated in vitro. Two preparations have been used; the transverse spinal cord slice preparation from the third or fourth lumbar segments of 14-16-day-old rats (71 cells) and a hemisected lumbar spinal cord preparation from 10-12-day-old rats (16 cells). The input impedances (range 11-128 M omega), membrane potentials (-67 +/- 8 mV S.D.), action potential amplitude (77 +/- 11.8 mV) duration (1.4 +/- 0.5 ms) and afterpotentials, were effectively identical in the neurons recorded from the two preparations. Neurons in both preparations when activated with long-duration (1-2 s) outward current pulses showed a single steady-state firing range with little adaptation of firing frequency or action potential amplitude. This pattern of responses was unaffected by changing the membrane potential. Orthodromic synaptic activity could be elicited in the neurons by stimulating either the small dorsal root remnants in the slice or the dorsal roots in the hemisected spinal cord. The responses evoked by single stimuli of increasing intensity varied in different neurons in both preparations. The commonest response (32/62) consisted of a short-latency, short-duration composite excitatory postsynaptic potential which generated one or two spikes with no further spiking activity at longer latency when the stimulus intensity was increased beyond threshold. In 20 neurons, graded stimulation produced a graded response with recruitment, at high intensities, of a discharge of action potentials lasting several hundred milliseconds. A small number of cells (4) responded to the single stimulus with a train of action potentials lasting several seconds. Stimulating adjacent dorsal roots in the hemisected cord preparation could evoke quite different responses from the neurons. The heterogeneity of the types of orthodromic responses obtained in both preparations, in spite of the almost uniform intrinsic membrane properties, is likely to reflect differences in the strength, location and type of afferent and interneuronal input to different dorsal horn cells.

背景与目标： : 已在体外研究了大鼠脊髓深背角 (laminae iii-vi) 中87个神经元的电生理特性。已使用两种制剂; 来自14-16天大的大鼠 (71个细胞) 的第三或第四腰椎节段的横向脊髓切片制剂和来自10-12天大的大鼠 (16个细胞) 的半腰脊髓制剂。输入阻抗 (范围11-128 M omega)，膜电位 (-67 +/- 8 mV s.d.)，动作电位振幅 (77 +/- 11.8 mV) 持续时间 (1.4 +/- 0.5 ms) 和后电位，两种制剂记录的神经元实际上是相同的。用长时间 (1-2 s) 的向外电流脉冲激活时，两种制剂中的神经元均显示出单一的稳态发射范围，几乎不适应发射频率或动作电位幅度。这种反应模式不受改变膜电位的影响。通过刺激切片中的小背根残余物或半脊髓中的背根，可以在神经元中引发正畸突触活动。在两种制剂中，强度增加的单个刺激引起的反应在不同的神经元中有所不同。最常见的反应 (32/62) 由短潜伏期，短持续时间的复合兴奋性突触后电位组成，当刺激强度增加超过阈值时，在更长的潜伏期产生一个或两个尖峰，而没有进一步的尖峰活动。在20个神经元中，分级刺激产生了分级反应，并在高强度下募集了持续数百毫秒的动作电位放电。少数细胞 (4) 对单个刺激有反应，持续了几秒钟的动作电位。在半切除的脐带制剂中刺激相邻的背根可能会引起神经元的完全不同的反应。尽管具有几乎均匀的固有膜特性，但在两种制剂中获得的正畸反应类型的异质性可能反映了不同背角细胞的传入和神经元输入的强度，位置和类型的差异。

BACKGROUND & AIMS: Background:Treatment of freezing of gait (FOG) is always challenging because of its unpredictable nature and multifactorial physiopathology. Intestinal levodopa infusion has been proposed in recent years as a valuable option for its improvement. FOG in Parkinson's disease (PD) can appear after deep brain stimulation in patients who never had gait symptoms. Objective:To study the effects of intestinal levodopa/carbidopa infusion in unresponsive-FOG that appears in PD patients treated with subthalamic nucleus deep brain stimulation. Methods:We retrospectively collected and analyzed demographic, clinical, and therapeutic data from five PD patients treated with subthalamic nucleus stimulation who developed unresponsive-FOG and received intestinal levodopa/carbidopa infusion as an alternative therapy. FOG was measured based on scores in item 14 of the Unified Parkinson's Disease Rating Scale before and after intestinal levodopa infusion. Results:Administration of intestinal levodopa caused improvement of FOG in the "ON" state in four patients (80%) by 2 or more points in item 14 of the Unified Parkinson's Disease Rating Scale. The improvement was maintained for at least 12 months. Conclusions:Intestinal levodopa infusion may be a valuable therapeutic option for unresponsive-FOG developed after subthalamic nucleus deep brain stimulation.

背景与目标：

BACKGROUND & AIMS: :Studies in non-human primates (NHPs) have led to major advances in our understanding of the function of the basal ganglia and of the pathophysiologic mechanisms of hypokinetic movement disorders such as Parkinson's disease and hyperkinetic disorders such as chorea and dystonia. Since the brains of NHPs are anatomically very close to those of humans, disease states and the effects of medical and surgical approaches, such as deep brain stimulation (DBS), can be more faithfully modeled in NHPs than in other species. According to the current model of the basal ganglia circuitry, which was strongly influenced by studies in NHPs, the basal ganglia are viewed as components of segregated networks that emanate from specific cortical areas, traverse the basal ganglia, and ventral thalamus, and return to the frontal cortex. Based on the presumed functional domains of the different cortical areas involved, these networks are designated as 'motor', 'oculomotor', 'associative' and 'limbic' circuits. The functions of these networks are strongly modulated by the release of dopamine in the striatum. Striatal dopamine release alters the activity of striatal projection neurons which, in turn, influences the (inhibitory) basal ganglia output. In parkinsonism, the loss of striatal dopamine results in the emergence of oscillatory burst patterns of firing of basal ganglia output neurons, increased synchrony of the discharge of neighboring basal ganglia neurons, and an overall increase in basal ganglia output. The relevance of these findings is supported by the demonstration, in NHP models of parkinsonism, of the antiparkinsonian effects of inactivation of the motor circuit at the level of the subthalamic nucleus, one of the major components of the basal ganglia. This finding also contributed strongly to the revival of the use of surgical interventions to treat patients with Parkinson's disease. While ablative procedures were first used for this purpose, they have now been largely replaced by DBS of the subthalamic nucleus or internal pallidal segment. These procedures are not only effective in the treatment of parkinsonism, but also in the treatment of hyperkinetic conditions (such as chorea or dystonia) which result from pathophysiologic changes different from those underlying Parkinson's disease. Thus, these interventions probably do not counteract specific aspects of the pathophysiology of movement disorders, but non-specifically remove the influence of the different types of disruptive basal ganglia output from the relatively intact portions of the motor circuitry downstream from the basal ganglia. Knowledge gained from studies in NHPs remains critical for our understanding of the pathophysiology of movement disorders, of the effects of DBS on brain network activity, and the development of better treatments for patients with movement disorders and other neurologic or psychiatric conditions.

背景与目标： : 对非人类灵长类动物 (NHPs) 的研究在我们对基底节的功能以及运动不足性疾病 (如帕金森氏病) 和运动亢进性疾病 (如舞蹈病和肌张力障碍) 的病理生理机制的理解方面取得了重大进展。由于NHPs的大脑在解剖学上与人类的大脑非常接近，因此与其他物种相比，疾病状态以及医学和外科手术方法 (例如深部脑刺激 (DBS)) 的影响可以在NHPs中更忠实地建模。根据受NHPs研究强烈影响的当前基底神经节回路模型，基底神经节被视为分离网络的组成部分，这些网络来自特定的皮质区域，穿过基底神经节和腹侧丘脑，然后返回额叶皮层。根据所涉及的不同皮质区域的假定功能域，这些网络被指定为 “运动”，“眼动”，“关联” 和 “边缘” 电路。这些网络的功能受到纹状体中多巴胺释放的强烈调节。纹状体多巴胺的释放会改变纹状体投射神经元的活性，进而影响 (抑制性) 基底神经节的输出。在帕金森氏病中，纹状体多巴胺的丧失导致基底神经节输出神经元放电的振荡爆发模式的出现，相邻基底神经节神经元放电的同步性增加以及基底神经节输出的总体增加。在帕金森氏症的NHP模型中，在丘脑底核 (基底神经节的主要组成部分之一) 水平上的运动回路失活的抗帕金森氏效应的证明了这些发现的相关性。这一发现也有力地促进了手术干预治疗帕金森氏病患者的复兴。虽然消融程序最初是为此目的使用的，但现在已被丘脑下核或苍白球内部节段的DBS所取代。这些程序不仅可有效治疗帕金森氏症，而且可有效治疗多动性疾病 (例如舞蹈病或肌张力障碍)，这些疾病是由与帕金森氏病不同的病理生理变化引起的。因此，这些干预措施可能不会抵消运动障碍的病理生理学的特定方面，而是非特异性地消除了基底神经节下游运动电路相对完整部分中不同类型的破坏性基底神经节输出的影响。从NHPs研究中获得的知识对于我们了解运动障碍的病理生理学，DBS对脑网络活动的影响以及为运动障碍和其他神经或精神疾病患者开发更好的治疗方法仍然至关重要。

BACKGROUND & AIMS: :L-shell ionisation and subsequent Coulomb explosion of fully deuterated methyl iodide, CD3I, irradiated with hard X-rays has been examined by a time-of-flight multi-ion coincidence technique. The core vacancies relax efficiently by Auger cascades, leading to charge states up to 16+. The dynamics of the Coulomb explosion process are investigated by calculating the ions' flight times numerically based on a geometric model of the experimental apparatus, for comparison with the experimental data. A parametric model of the explosion, previously introduced for multi-photon induced Coulomb explosion, is applied in numerical simulations, giving good agreement with the experimental results for medium charge states. Deviations for higher charges suggest the need to include nuclear motion in a putatively more complete model. Detection efficiency corrections from the simulations are used to determine the true distributions of molecular charge states produced by initial L1, L2 and L3 ionisation.

背景与目标： : 已通过飞行时间多离子重合技术检查了用硬x射线辐照的全氘代甲基碘CD3I的L壳电离和随后的库仑爆炸。螺旋钻级联有效地放松了核心空位，导致充电状态高达16 +。通过基于实验设备的几何模型数值计算离子的飞行时间，研究了库仑爆炸过程的动力学，以与实验数据进行比较。在数值模拟中应用了先前针对多光子引起的库仑爆炸引入的爆炸参数模型，与中等电荷状态的实验结果非常吻合。较高电荷的偏差表明需要将核运动包括在一个更完整的模型中。来自模拟的检测效率校正用于确定由初始L1，L2和L3电离产生的分子电荷态的真实分布。

BACKGROUND & AIMS: :Slow deep breathing (SDB) is commonly employed in the management of pain, but the underlying mechanisms remain equivocal. This study sought to investigate effects of instructed breathing patterns on experimental heat pain and to explore possible mechanisms of action. In a within-subject experimental design, healthy volunteers (n = 48) performed 4 breathing patterns: 1) unpaced breathing, 2) paced breathing (PB) at the participant's spontaneous breathing frequency, 3) SDB at 6 breaths per minute with a high inspiration/expiration ratio (SDB-H), and 4) SDB at 6 breaths per minute with a low inspiration/expiration ratio (SDB-L). During presentation of each breathing pattern, participants received painful heat stimuli of 3 different temperatures and rated each stimulus on pain intensity. Respiration, heart rate, and blood pressure were recorded. Compared to unpaced breathing, participants reported less intense pain during each of the 3 instructed breathing patterns. Among the instructed breathing patterns, pain did not differ between PB and SDB-H, and SDB-L attenuated pain more than the PB and SDB-H patterns. The latter effect was paralleled by greater blood pressure variability and baroreflex effectiveness index during SDB-L. Cardiovascular changes did not mediate the observed effects of breathing patterns on pain. PERSPECTIVES: SDB is more efficacious to attenuate pain when breathing is paced at a slow rhythm with an expiration that is long relative to inspiration, but the underlying mechanisms remain to be elucidated.

背景与目标： : 缓慢深呼吸 (SDB) 通常用于治疗疼痛，但潜在的机制仍然模棱两可。本研究旨在研究指示呼吸方式对实验性热痛的影响，并探索可能的作用机制。在受试者内部的实验设计中，健康志愿者 (n   =   48) 进行了4种呼吸模式: 1) 无节奏呼吸，2) 以参与者的自发呼吸频率进行有节奏的呼吸 (PB)，3) SDB，每分钟6次呼吸，具有高吸气/呼气比 (sdb-h)，和4) SDB，每分钟6次呼吸，具有低吸气/呼气比 (sdb-l)。在呈现每种呼吸模式期间，参与者接受了3种不同温度的疼痛性热刺激，并根据疼痛强度对每种刺激进行了评分。记录呼吸，心率和血压。与无节奏呼吸相比，参与者在3种指示的呼吸模式中的每一种都报告了较少的剧烈疼痛。在指示的呼吸模式中，PB和sdb-h之间的疼痛没有差异，sdb-l减轻的疼痛比PB和sdb-h模式更大。后者的作用与sdb-l期间更大的血压变异性和压力反射有效性指数平行。心血管变化不能介导观察到的呼吸模式对疼痛的影响。观点: 当呼吸以缓慢的节律起搏，相对于吸气而言，呼气时间较长时，SDB更有效地减轻疼痛，但潜在的机制仍有待阐明。

BACKGROUND & AIMS: :Prescribed burning is a common management tool to control fuel loads, ground vegetation, and facilitate desirable game species. We evaluated soil fungal community responses to long-term prescribed fire treatments in a loblolly pine forest on the Piedmont of Georgia and utilized deep Internal Transcribed Spacer Region 1 (ITS1) amplicon sequencing afforded by the recent Ion Torrent Personal Genome Machine (PGM). These deep sequence data (19,000 + reads per sample after subsampling) indicate that frequent fires (3-year fire interval) shift soil fungus communities, whereas infrequent fires (6-year fire interval) permit system resetting to a state similar to that without prescribed fire. Furthermore, in nonmetric multidimensional scaling analyses, primarily ectomycorrhizal taxa were correlated with axes associated with long fire intervals, whereas soil saprobes tended to be correlated with the frequent fire recurrence. We conclude that (1) multiplexed Ion Torrent PGM analyses allow deep cost effective sequencing of fungal communities but may suffer from short read lengths and inconsistent sequence quality adjacent to the sequencing adaptor; (2) frequent prescribed fires elicit a shift in soil fungal communities; and (3) such shifts do not occur when fire intervals are longer. Our results emphasize the general responsiveness of these forests to management, and the importance of fire return intervals in meeting management objectives.

背景与目标： : 规定燃烧是一种常见的管理工具，可控制燃料负荷，地面植被并促进理想的游戏物种。我们评估了佐治亚州皮埃蒙特的火炬松森林中土壤真菌群落对长期规定的火处理的反应，并利用了最近的离子洪流个人基因组机器 (PGM) 提供的深层内部转录间隔区1 (ITS1) 扩增子测序。这些深度序列数据 (子采样后每个样本读取19,000个读数) 表明，频繁的火灾 (3年火灾间隔) 改变了土壤真菌群落，而不频繁的火灾 (6年火灾间隔) 允许系统重置为类似于没有规定的状态火。此外，在非度量多维标度分析中，主要是外生菌根类群与长火灾间隔相关的轴相关，而土壤腐生倾向于与频繁的火灾复发相关。我们得出的结论是 :( 1) 多重离子激流PGM分析允许对真菌群落进行深度经济有效的测序，但可能遭受短的读取长度和与测序适配器相邻的序列质量不一致的困扰; (2) 频繁的规定火灾引起土壤真菌群落的转变; (3) 当火灾间隔较长时，不会发生这种变化。我们的结果强调了这些森林对管理的总体响应能力，以及回火间隔在实现管理目标中的重要性。

BACKGROUND & AIMS: :The oxygenated hypolimnion accounts for a volumetrically significant part of the global freshwater systems. Previous studies have proposed the presence of hypolimnion-specific bacterioplankton lineages that are distinct from those inhabiting the epilimnion. To date, however, no consensus exists regarding their ubiquity and abundance, which is necessary to evaluate their ecological importance. The present study investigated the bacterioplankton community in the oxygenated hypolimnia of 10 deep freshwater lakes. Despite the broad geochemical characteristics of the lakes, 16S rRNA gene sequencing demonstrated that the communities in the oxygenated hypolimnia were distinct from those in the epilimnia and identified several predominant lineages inhabiting multiple lakes. Catalyzed reporter deposition fluorescence in situ hybridization revealed that abundant hypolimnion-specific lineages, CL500-11 (Chloroflexi), CL500-3, CL500-37, CL500-15 (Planctomycetes) and Marine Group I (Thaumarchaeota), together accounted for 1.5-32.9% of all bacterioplankton in the hypolimnion of the lakes. Furthermore, an analysis of single-nucleotide variation in the partial 16S rRNA gene sequence (oligotyping) suggested the presence of different sub-populations between lakes and water layers among the lineages occurring in the entire water layer (for example, acI-B1 and acI-A7). Collectively, these results provide the first comprehensive overview of the bacterioplankton community in the oxygenated hypolimnion of deep freshwater lakes.

背景与目标： : 含氧的低水离子在全球淡水系统中占很大一部分。先前的研究已经提出，存在特定于hypolimnion的浮游细菌谱系，这些谱系与居住在epilimnion的细菌谱系不同。然而，迄今为止，关于它们的普遍性和丰富性尚无共识，这是评估其生态重要性所必需的。本研究调查了10个深淡水湖的含氧低泡中的浮游细菌群落。尽管湖泊具有广泛的地球化学特征，但16S rRNA基因测序表明，含氧的低水草中的群落与上水草中的群落不同，并确定了居住在多个湖泊中的几个主要谱系。催化的报告分子沉积荧光原位杂交显示，丰富的hypolinion特异性谱系，CL500-11 (Chloroflexi)，CL500-3，CL500-37，CL500-15 (planctoycetes) 和海洋I类 (Thaumarchaeota)，占所有浮游细菌的1.5-32.9% 在湖泊的hypolinion中。此外，对部分16 srrna基因序列中的单核苷酸变异的分析 (寡核苷酸分型) 表明，在整个水层中发生的谱系 (例如，acI-B1和acI-A7) 中，湖泊和水层之间存在不同的亚群。总的来说，这些结果首次全面概述了深淡水湖含氧的低水量中的浮游细菌群落。

BACKGROUND & AIMS: OBJECTIVE:Type 2 diabetes (T2D) is a complex disease characterized by pancreatic islet dysfunction, insulin resistance, and disruption of blood glucose levels. Genome-wide association studies (GWAS) have identified > 400 independent signals that encode genetic predisposition. More than 90% of associated single-nucleotide polymorphisms (SNPs) localize to non-coding regions and are enriched in chromatin-defined islet enhancer elements, indicating a strong transcriptional regulatory component to disease susceptibility. Pancreatic islets are a mixture of cell types that express distinct hormonal programs, so each cell type may contribute differentially to the underlying regulatory processes that modulate T2D-associated transcriptional circuits. Existing chromatin profiling methods such as ATAC-seq and DNase-seq, applied to islets in bulk, produce aggregate profiles that mask important cellular and regulatory heterogeneity. METHODS:We present genome-wide single-cell chromatin accessibility profiles in >1,600 cells derived from a human pancreatic islet sample using single-cell combinatorial indexing ATAC-seq (sci-ATAC-seq). We also developed a deep learning model based on U-Net architecture to accurately predict open chromatin peak calls in rare cell populations. RESULTS:We show that sci-ATAC-seq profiles allow us to deconvolve alpha, beta, and delta cell populations and identify cell-type-specific regulatory signatures underlying T2D. Particularly, T2D GWAS SNPs are significantly enriched in beta cell-specific and across cell-type shared islet open chromatin, but not in alpha or delta cell-specific open chromatin. We also demonstrate, using less abundant delta cells, that deep learning models can improve signal recovery and feature reconstruction of rarer cell populations. Finally, we use co-accessibility measures to nominate the cell-specific target genes at 104 non-coding T2D GWAS signals. CONCLUSIONS:Collectively, we identify the islet cell type of action across genetic signals of T2D predisposition and provide higher-resolution mechanistic insights into genetically encoded risk pathways.

背景与目标：

BACKGROUND & AIMS: :NrS-1 is the first known phage that can infect Epsilonproteobacteria, one of the predominant primary producers in the deep-sea hydrothermal vent ecosystems. NrS-1 polymerase is a multidomain enzyme and is one key component of the phage replisome. The N-terminal Prim/Pol and HBD domains are responsible for DNA polymerization and de novo primer synthesis activities of NrS-1 polymerase. However, the structure and function of the C-terminus (CTR) of NrS-1 polymerase are poorly understood. Here, we report two crystal structures, showing that NrS-1 CTR adopts one unique hexameric ring-shaped conformation. Although the central helicase domain of NrS-1 CTR shares structural similarity with the superfamily III helicases, the folds of the Head and Tail domains are completely novel. Via mutagenesis and in vitro biochemical analysis, we identified many residues important for the helicase and polymerization activities of NrS-1 polymerase. In addition to NrS-1 polymerase, our study may also help us identify and understand the functions of multidomain polymerases expressed by many NrS-1 related phages.

背景与目标： : NrS-1是第一个可以感染Epsilonproteobacteria的噬菌体，Epsilonproteobacteria是深海热液喷口生态系统的主要初级生产者之一。NrS-1聚合酶是一种多结构域酶，是噬菌体复制体的关键成分之一。N末端Prim/Pol和HBD结构域负责NrS-1聚合酶的DNA聚合和从头引物合成活性。然而，对NrS-1聚合酶的C末端 (CTR) 的结构和功能知之甚少。在这里，我们报告了两种晶体结构，表明NrS-1 CTR采用一种独特的六聚体环形构象。尽管NrS-1 CTR的中央解旋酶结构域与超家族III解旋酶具有结构相似性，但头和尾结构域的褶皱是完全新颖的。通过诱变和体外生化分析，我们确定了许多对NrS-1聚合酶的解旋酶和聚合活性重要的残基。除了NrS-1聚合酶之外，我们的研究还可能帮助我们鉴定和理解许多NrS-1相关噬菌体表达的多域聚合酶的功能。

BACKGROUND & AIMS: Background:Deep brain stimulation is a surgical treatment for Parkinson's disease. Its impacts on motor symptoms are widely reported; however, little is known about the broader impact of deep brain stimulation on the community lives of people with Parkinson's disease. Lifespace is a measure of lived community mobility, providing an indication of community access and participation. Aims:This pilot study explored the feasibility of remotely monitoring the qualitative and quantitative community outcomes related to deep brain stimulation. Methods:A longitudinal mixed methods study with a convergent design was undertaken exploring the lifespace, quality of life, life satisfaction and lived experiences of people with Parkinson's disease before and after deep brain stimulation. Data were collected through questionnaires, semi-structured interviews and a smartphone-based application which collected geolocation data. Results:Quantitative and qualitative data from eight participants living with Parkinson's disease were analysed and integrated. At baseline, participants had a median age of 68 years and a median Hoehn and Yahr score of 2. Measuring a range of community-based outcomes indicated different change trajectories for individuals across outcomes. Key content areas were developed from the qualitative data: participation in occupations and travel and home. This study indicates the potential value of including geolocation data-based lifespace collection in metropolitan and regional areas. Conclusions:Monitoring lifespace in conjunction with subjective measures provides insights into the complex and individually varied experiences. Further research could explore the impacts of deep brain stimulation on occupations and community participation to gain a deeper understanding of the related needs and support clinical approaches.

背景与目标：

BACKGROUND & AIMS: :Deep brain stimulation (DBS) is an effective neurosurgical treatment for patients with advanced Parkinson's disease (PD) suffering from motor complications that are refractory to further medication management. DBS requires an invasive procedure of implanting brain electrodes while awake, followed by implantation of neurostimulators under general anesthesia. The neurostimulator requires battery monitoring and replacement approximately every 3 to 5 years. These two elements of the technology provide numerous decision points about continuing therapies that can involve ethical choices. Although motor function can be improved with subthalamic nucleus (STN) DBS, the long-term risks of living with implanted hardware should be carefully evaluated for patients with diminishing cognitive capacity. We describe two cases where ethical dilemmas occurred postoperatively as a result of cognitive decline and describe salient ethical dimensions that illustrate the need for a proactive postoperative plan for supervision as a prerequisite for surgery to include neuropsychological testing to predict the likelihood of net benefit to the patient and family beyond just motor improvement.

背景与目标： : 深部脑刺激 (DBS) 是一种有效的神经外科治疗方法，用于患有运动并发症的晚期帕金森氏病 (PD) 患者，这些并发症难以进一步治疗药物。DBS需要在清醒时植入脑电极的侵入性程序，然后在全身麻醉下植入神经刺激器。神经刺激器需要大约每3至5年进行一次电池监测和更换。该技术的这两个要素提供了许多有关可能涉及道德选择的持续疗法的决策点。尽管丘脑底核 (STN) DBS可以改善运动功能，但对于认知能力下降的患者，应仔细评估植入硬件的长期风险。我们描述了两种情况，其中由于认知能力下降而在术后发生伦理困境，并描述了突出的伦理维度，这些维度说明了需要积极的术后监督计划作为手术的先决条件，包括神经心理学测试，以预测对患者和家庭的净收益的可能性，而不仅仅是运动改善。