Hasil untuk "Neurosciences. Biological psychiatry. Neuropsychiatry"

Michael Jirasek, Abhishek Sharma, Mary Wong et al.

Selection is central to biological evolution, yet there has been no general experimental framework for quantifying selection in chemical systems before life. Here we demonstrate that selection in a prebiological chemical system can be directly quantified. Assembly Theory predicts that selection corresponds to a transition from undirected to directed exploration of chemical possibility space, measurable through the amount of Assembly, A, which integrates molecular assembly index with observed copy number. By analysing peptide ensembles produced under diverse polymerisation conditions, we show that undirected reactions explore sequence space almost uniformly, yielding exploration ratios of 0.85-0.95, whereas reactions influenced by evolved proteases generate markedly lower ratios (0.51-0.75) and elevated A, consistent with selective reinforcement of specific assembly pathways. Across multiple environments and amino-acid combinations, the exploration ratio and ensemble assembly A robustly distinguish directed from undirected exploration, establishing a general, experimentally tractable metric for detecting and measuring selection in chemical evolution.

Guifeng Zhuo, Wei Chen, Yanan Hu et al.

ABSTRACT Background and Objectives A variety of observational studies suggest a possible connection between C‐X‐C Motif Chemokine Ligand 5 (CXCL5) and vascular dementia (VaD), though the exact causal relationship is still uncertain. This research aims to investigate the causal connection between CXCL5 and VaD risk through a Mendelian randomization (MR) method and to examine the phosphate‐to‐glucose ratio as a possible mediator. Methods Using summary‐level data from genome‐wide association studies (GWAS), we conducted a two‐sample MR analysis to investigate the genetic prediction of CXCL5 and VaD. Horizontal pleiotropy, heterogeneity, and sensitivity analyses were also performed on the MR findings. Additionally, a two‐step MR was utilized to quantify the proportion of the effect of CXCL5 on VaD mediated by the phosphate‐to‐glucose ratio. Results MR analysis identified that higher levels of CXCL5 (IVW: p = 0.022, OR = 1.265, 95% CI = 1.034–1.547) increase the risk of VaD. Tests for horizontal pleiotropy (p > 0.05), heterogeneity (p > 0.05), and sensitivity analyses supported these findings. There is insufficient robust evidence to suggest that genetic predispositions for VaD have any significant impact on CXCL5 (IVW: p = 0.254). The phosphate‐to‐glucose ratio accounted for 11.1% of increase in the risk of VaD associated with CXCL5 (95% CI = −12.3% to 34.5%). Conclusion To conclude, our research confirms a causal link between CXCL5 and VaD and shows that the ratio of phosphate‐to‐glucose plays a mediating role in a segment of the risk effect of CXCL5 on VaD. However, most of the effects of CXCL5 on VaD are still not well understood. Additional studies are necessary to explore other potential mediators as risk factors. In clinical settings, individuals with abnormally elevated CXCL5 may need to be monitored for an increased risk of developing VaD.

Amirhosein Sotoodehfar, Rishabh, Hadi Zadeh-Haghighi et al.

Recent studies in vitro and in vivo suggest that flavin adenine dinucleotide (FAD) on its own might be able to act as a biological magnetic field sensor. Motivated by these observations, in this study, we develop a detailed quantum theoretical model for the radical pair mechanism (RPM) for the flavin adenine biradical within the FAD molecule. We perform molecular dynamics simulations to determine the distance between the radicals on FAD, which we then feed into a quantum master equation treatment of the RPM. In contrast to previous semi-classical models which are limited to the low-field and high-field cases, our quantum model can predict the full magnetic field dependence of the transient absorption signal. Our model's predictions are consistent with experiments.

Md Sayed Tanveer, Dhruvik Patel, Hunter E. Schweiger et al.

With the recent advancements in artificial intelligence, researchers and industries are deploying gigantic models trained on billions of samples. While training these models consumes a huge amount of energy, human brains produce similar outputs (along with other capabilities) with massively lower data and energy requirements. For this reason, more researchers are increasingly considering alternatives. One of these alternatives is known as synthetic biological intelligence, which involves training \textit{in vitro} neurons for goal-directed tasks. This multidisciplinary field requires knowledge of tissue engineering, bio-materials, digital signal processing, computer programming, neuroscience, and even artificial intelligence. The multidisciplinary requirements make starting synthetic biological intelligence research highly non-trivial and time-consuming. Generally, most labs either specialize in the biological aspects or the computational ones. Here, we propose how a lab focusing on computational aspects, including machine learning and device interfacing, can start working on synthetic biological intelligence, including organoid intelligence. We will also discuss computational aspects, which can be helpful for labs that focus on biological research. To facilitate synthetic biological intelligence research, we will describe such a general process step by step, including risks and precautions that could lead to substantial delay or additional cost.

Dalila Mango, Robert Nisticò

Angélica Uscátegui Daccarett., J. Sebastián Ortiz De La Rosa., Laura Victoria Guío Mahecha.

Se presenta una revisión de la literatura acerca de la presencia de alteración del campo visual asociada al uso de vigabatrín como antiepiléptico. Considerando las precauciones de prescripción derivadas de los efectos visuales de vigabatrin, presentamos una revisión no sistemática que muestra los principales datos respecto a prevalencia, factores de riesgo, fisiopatología y seguimiento de esta alteración. La prevalencia de aparición de la retinopatía es variable según las series revisadas, y los factores de riesgo como uso de dosis máxima, dosis acumulada y edad no están claramente demostrados, por lo que se considera a éste un efecto idiosincrático. Se recomienda la vigilancia oftalmológica y campimétrica periódica.

Natalia Smith-Cortinez, Natalia Smith-Cortinez, Ferry G. J. Hendriksen et al.

IntroductionThe leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) is a tissue resident stem cell marker, which it is expressed in supporting cells (SCs) in the organ of Corti in the mammalian inner ear. These LGR5+ SCs can be used as an endogenous source of progenitor cells for regeneration of hair cells (HCs) to treat hearing loss and deafness. We have recently reported that LGR5+ SCs survive 1 week after ototoxic trauma. Here, we evaluated Lgr5 expression in the adult cochlea and long-term survival of LGR5+ SCs following severe hearing loss.MethodsLgr5GFP transgenic mice and wild type mice aged postnatal day 30 (P30) and P200 were used. P30 animals were deafened with a single dose of furosemide and kanamycin. Seven and 28 days after deafening, auditory brainstem responses (ABRs) were recorded. Cochleas were harvested to characterize mature HCs and LGR5+ SCs by immunofluorescence microscopy and quantitative reverse transcription PCR (q-RT-PCR).ResultsThere were no significant age-related changes in Lgr5 expression when comparing normal-hearing (NH) mice aged P200 with P30. Seven and 28 days after ototoxic trauma, there was severe outer HC loss and LGR5 was expressed in the third row of Deiters’ cells and in inner pillar cells. Seven days after induction of ototoxic trauma there was an up-regulation of the mRNA expression of Lgr5 compared to the NH condition; 28 days after ototoxic trauma Lgr5 expression was similar to NH levels.DiscussionThe presence of LGR5+ SCs in the adult mouse cochlea, which persists after severe HC loss, suggests potential regenerative capacity of endogenous cochlear progenitor cells in adulthood. To our knowledge, this is the first study showing not only long-term survival of LGR5+ SCs in the normal and ototoxically damaged cochlea, but also increased Lgr5 expression in the adult mouse cochlea after deafening, suggesting long-term availability of potential target cells for future regenerative therapies.

Pawel Romanczuk, Bryan C. Daniels

Collective behaviors exhibited by animal groups, such as fish schools, bird flocks, or insect swarms are fascinating examples of self-organization in biology. Concepts and methods from statistical physics have been used to argue theoretically about the potential consequences of collective effects in such living systems. In particular, it has been proposed that such collective systems should operate close to a phase transition, specifically a (pseudo-)critical point, in order to optimize their capability for collective computation. In this chapter, we will first review relevant phase transitions exhibited by animal collectives, pointing out the difficulties of applying concepts from statistical physics to biological systems. Then we will discuss the current state of research on the "criticality hypothesis", including methods for how to measure distance from criticality and specific functional consequences for animal groups operating near a phase transition. We will highlight the emerging view that de-emphasizes the optimality of being exactly at a critical point and instead explores the potential benefits of living systems being able to tune to an optimal distance from criticality. We will close by laying out future challenges for studying collective behavior at the interface of physics and biology.

Shivang Agarwal, Daniel R. Kattnig, Clarice D. Aiello et al.

The Posner molecule (calcium phosphate trimer), has been hypothesized to function as a biological quantum information processor due to its supposedly long-lived entangled $^{31}$P nuclear spin states. This hypothesis was challenged by our recent finding that the molecule lacks a well-defined rotational axis of symmetry -- an essential assumption in the proposal for Posner-mediated neural processing -- and exists as an asymmetric dynamical ensemble. Following up, we investigate here the spin dynamics of the molecule's entangled $^{31}$P nuclear spins within the asymmetric ensemble. Our simulations show that entanglement between two nuclear spins prepared in a Bell state in separate Posner molecules decays on a sub-second timescale -- much faster than previously hypothesized, and not long enough for super-cellular neuronal processing. Calcium phosphate dimers however, are found to be surprisingly resilient to decoherence and are able to preserve entangled nuclear spins for hundreds of seconds, suggesting that neural processing might occur through them instead.

Xiaoxuan Cai, Xinru Wang, Li Zeng et al.

Mobile technology enables unprecedented continuous monitoring of an individual's behavior, social interactions, symptoms, and other health conditions, presenting an enormous opportunity for therapeutic advancements and scientific discoveries regarding the etiology of psychiatric illness. Continuous collection of mobile data results in the generation of a new type of data: entangled multivariate time series of outcome, exposure, and covariates. Missing data is a pervasive problem in biomedical and social science research, and the Ecological Momentary Assessment (EMA) using mobile devices in psychiatric research is no exception. However, the complex structure of multivariate time series introduces new challenges in handling missing data for proper causal inference. Data imputation is commonly recommended to enhance data utility and estimation efficiency. The majority of available imputation methods are either designed for longitudinal data with limited follow-up times or for stationary time series, which are incompatible with potentially non-stationary time series. In the field of psychiatry, non-stationary data are frequently encountered as symptoms and treatment regimens may experience dramatic changes over time. To address missing data in possibly non-stationary multivariate time series, we propose a novel multiple imputation strategy based on the state space model (SSMmp) and a more computationally efficient variant (SSMimpute). We demonstrate their advantages over other widely used missing data strategies by evaluating their theoretical properties and empirical performance in simulations of both stationary and non-stationary time series, subject to various missing mechanisms. We apply the SSMimpute to investigate the association between social network size and negative mood using a multi-year observational smartphone study of bipolar patients, controlling for confounding variables.

Juliana Tessari Dias Rohr, Juliana Tessari Dias Rohr, Cassiano Rodrigues Isaac et al.

Despite the various perceptual-motor deficits documented in strabismus, there is a paucity of studies evaluating visual illusions in patients with strabismus. The aim of this study was to examine how the illusionary perception occurs in children/adolescents (10–15 years old) with strabismus with referral for surgery to correct ocular deviations. A controlled cross-sectional study was carried out in which 45 participants with strabismus and 62 healthy volunteers aged 10–15 years were evaluated. The behavioral response to three geometric illusions [Vertical-Horizontal illusion, Müller-Lyer illusion (Bretano version) and Ponzo illusion] and respective neutral stimuli (non-illusory images) regarding the estimation of image size and response time were measured using the Method of Adjustment. To analyze the influence of secondary factors: type of ocular deviation (convergent, divergent or associated with vertical deviation); amount of eye deviation; presence of amblyopia and stereopsis, a one-way ANOVA was performed. Among the tested illusions, children with strabismus showed greater susceptibility (p = 0.006) and response time (p = 0.004) to Ponzo’s illusory images. Children with strabismus and preserved stereopsis, on the other hand, showed similar susceptibility and response time to control group patients to the Ponzo illusion (p < 0.005). Patients with amblyopia showed overcorrection in the estimate of non-illusory Ponzo images (p = 0.046). Children with horizontal ocular deviation (esotropia or exotropia) associated with vertical deviation (hypertropia, DVD and/or alphabetical anisotropy) showed higher susceptibility to vertical adjustment images for the Müller-Lyer illusion (Brentano version) (p = 0.017). Individuals with strabismus tended to overcorrect the length of the straight-line segment adjusted for non-illusory images when testing non-illusory images in the Müller-Lyer test (Brentano version) (p = 0.009), as well as for the neutral images in the Vertical-Horizontal test (p = 0.000). The findings indicated impairment in the perception of geometric illusions and neutral figures, especially for the Ponzo illusion test by children with strabismus. As the behavioral response to illusory images may indirectly reflect the visual and morphofunctional alterations present in these individuals, we suggest that the investigation of visual illusory perception can be used as a new research strategy in the field of investigating the visual function in strabismus.

Fernando L. Pagan, Yasar Torres‐Yaghi, Michaeline L. Hebron et al.

Abstract Introduction Bosutinib, a dual Abelson/Src inhibitor, was investigated in individuals with dementia with Lewy bodies (DLB). Methods A single site, randomized, double‐blind, placebo‐controlled study of the effects of oral bosutinib, 100 mg once daily for 12 weeks on primary safety and pharmacokinetics and secondary biomarker outcomes. Results Twenty‐six participants were randomized and included male and female (12:1) in the bosutinib arm and all male (13) in the placebo arm. The average age was 72.9 ± 8.1 (year ± standard deviation). There were no serious adverse events and no dropouts. Bosutinib was measured in the cerebrospinal fluid (CSF) and inhibited Abelson. Bosutinib reduced CSF alpha‐synuclein and dopamine catabolism. Discussion Bosutinib is safe and well tolerated and penetrates the blood–brain barrier to inhibit Abelson and reduce CSF alpha‐synuclein and dopamine catabolism, suggesting that bosutinib (100 mg) may be at or near the lowest effective dose in DLB. These results will guide adequately powered studies to determine the efficacy of a dose range of bosutinib and longer treatment in DLB. Highlights Bosutinib is a dual Abl/Src inhibitor that penetrates the blood brain barrier Bosutinib is safe and tolerated in individuals with dementia with Lewy bodies Bosutinib engages its target via inhibition of Abl and Src Bosutinib reduces CSF alpha‐synuclein and attenuates breakdown of dopamine Bosutinib improves activities of daily living in dementia with Lewy bodies

Shourong Lu, Ying Yang, Qiao Xu et al.

Gut microbial alteration is closely associated with brain disorders including cognitive impairment (CI). Gut microbes have the potential to predicate the development of diseases. However, the gut microbial markers for CI remain to be elucidated. In this study, the gut microbial alterations were assessed using16S rRNA sequencing, and identified the gut microbial markers using a random forest model. The results showed that there were significant gut microbial differences between the control and CI groups based on beta diversity (p < 0.002). Patients with CI had higher abundances of Actinobacteria and Proteobacteria but lower proportions of Bcateroidetes and Firmicutes vs. that in the control group. Patients had 39 special genera and the control subjects had 11 special genera. Furthermore, 11 genera such as Blautia, Roseburia, and Lactococcus and 18 genera such as Lactobacillus, Ruminococcus 2, and Akkermansia were the differential taxa in the control and CI groups, respectively. Gene functions related to nutrient metabolisms were upregulated in patients with CI. This suggested that the huge differences in gut microbes between the two groups and gut microbiota had the potential to predicate the development of CI. Based on machine learning results, 15 genera such as Lactobacillus, Bifidobacterium, and Akkermansia were selected as the optimal marker set to predicate CI with an area under curve (AUC) value of 78.4%. The results revealed the gut microbial markers for CI and provided a potential diagnosis tool to prevent the development of CI in the elderly.

Ben Baker, Benjamin Lansdell, Konrad Kording

Neuroscientists often describe neural activity as a representation of something, or claim to have found evidence for a neural representation. But what do these statements mean? The reasons to call some neural activity a representation and the assumptions that come with this term are not generally made clear from its common uses in neuroscience. Representation is a central concept in philosophy of mind, with a rich history going back to the ancient period. In order to clarify its usage in neuroscience, here we advance a link between the connotations of this term across these disciplines. We draw on a broad range of discourse in philosophy to distinguish three key aspects of representation: correspondence, functional role, and teleology. We argue that each of these aspects are implied by the explanatory role the term plays in neuroscience. However, evidence related to all three aspects is rarely presented or discussed in the course of individual studies that aim to identify representations. Overlooking the significance of all three aspects hinders communication in neuroscience, as it obscures the limitations of experimental paradigms and conceals gaps in our understanding of the phenomena of primary interest. Working from this three-part view, we discuss how to move toward clearer communication about representations in the brain.

Arthur Freitas Brandão, Ivan José Magayewski Bonet, Marco Pagliusi et al.

Recent findings from rodent studies suggest that high-fat diet (HFD) increases hyperalgesia independent of obesity status. Furthermore, weight loss interventions such as voluntary physical activity (PA) for adults with obesity or overweight was reported to promote pain reduction in humans with chronic pain. However, regardless of obesity status, it is not known whether HFD intake and sedentary (SED) behavior is underlies chronic pain susceptibility. Moreover, differential gene expression in the nucleus accumbens (NAc) plays a crucial role in chronic pain susceptibility. Thus, the present study used an adapted model of the inflammatory prostaglandin E2 (PGE2)-induced persistent hyperalgesia short-term (PH-ST) protocol for mice, an HFD, and a voluntary PA paradigm to test these hypotheses. Therefore, we performed an analysis of differential gene expression using a transcriptome approach of the NAc. We also applied a gene ontology enrichment tools to identify biological processes associated with chronic pain susceptibility and to investigate the interaction between the factors studied: diet (standard diet vs. HFD), physical activity behavior (SED vs. PA) and PH-ST (PGE vs. saline). Our results demonstrated that HFD intake and sedentary behavior promoted chronic pain susceptibility, which in turn was prevented by voluntary physical activity, even when the animals were fed an HFD. The transcriptome of the NAc found 2,204 differential expression genes and gene ontology enrichment analysis revealed 41 biologic processes implicated in chronic pain susceptibility. Taking these biological processes together, our results suggest that genes related to metabolic and mitochondria stress were up-regulated in the chronic pain susceptibility group (SED-HFD-PGE), whereas genes related to neuroplasticity were up-regulated in the non-chronic pain susceptibility group (PA-HFD-PGE). These findings provide pieces of evidence that HFD intake and sedentary behavior provoked gene expression changes in the NAc related to promotion of chronic pain susceptibility, whereas voluntary physical activity provoked gene expression changes in the NAc related to prevention of chronic pain susceptibility. Finally, our findings confirmed previous literature supporting the crucial role of voluntary physical activity to prevent chronic pain and suggest that low levels of voluntary physical activity would be helpful and highly recommended as a complementary treatment for those with chronic pain.

Xiaoming Wang, Xiaoming Wang, Shaojuan Cui et al.

BackgroundDysfunctional beliefs about the self are common in the development of depressive symptoms, but it remains unclear how depressed patients respond to unfair treatment, both dispositionally and neurally. The present research is an attempt to explore the differences in sensitivity to injustice as a victim and its neural correlates in patients with major depressive disorder (MDD) versus healthy controls.MethodsFirst episodic, drug-naïve patients with MDD (n = 30) and a control group (n = 30) were recruited to compare their differences in victim sensitivity. A second group of patients with MDD (n = 23) and their controls (n = 28) were recruited to replicate the findings and completed resting-state functional magnetic resonance imaging (fMRI) scanning. Spontaneous brain activity measured by fractional amplitude of low-frequency fluctuation (fALFF) was used to characterize the neural correlates of victim sensitivity both in patients and in healthy controls.ResultsHigher victim sensitivity was consistently found in patients with MDD than healthy controls in both datasets. Multiple regression analysis on the fALFF showed a significant interaction effect between diagnosis and victim sensitivity in the right dorsolateral prefrontal cortex (DLPFC).ConclusionsThe patients with MDD show higher sensitivity to injustice as a victim, which may be independent of their disease course. The MDD patients differ from healthy controls in the neural correlates of victim sensitivity. These findings shed light on the linkage between cognitive control subserved by the DLPFC and negative bias towards the self implicated by higher victim sensitivity among the depressed patients.

Rahul Pillai, Bijesh Ravindran Nair, Prasad Kanna Prabhakar et al.

Context: The iliac crest (IC) is widely used as an autograft for bony fusion in spine surgeries. The pain after IC harvesting is severe enough to delay ambulation and thus hospital discharge. Aim: This study aimed to determine the effect of a transmuscular quadratus lumborum block (QLB) on postoperative ambulation in patients undergoing anterior IC bone graft harvesting. Settings and Design: This was a retrospective study of patients who underwent cervical corpectomy and fusion with anterior IC bone graft over a period of 3 years. Materials and Methods: Group A was patients who received QLB for anterior IC bone graft harvest site pain, and those who did not receive QLB were Group B. The primary outcome was the time taken for ambulation, and the secondary outcomes compared were the pain scores, hemodynamics, and the duration of hospital stay. Results: A total of 34 patients were studied, of which 17 patients received QLB (Group A) and the rest 17 did not receive QLB (Group B). The demographics, preoperative and intraoperative variables, and the pain score were comparable between the groups. The patients in the QLB group ambulated early as compared to Group B (1.5 ± 0.7 vs. 2.4 ± 0.9 days = 0.002). Further, the duration of postoperative hospitalization was shorter in the former as compared to the latter (3.8 ± 1.6 vs. 5.1 ± 2.1 days; P = 0.054). There were no complications related to the QLB. Conclusion: The administration of QLB resulted in earlier postoperative ambulation in patients undergoing cervical corpectomy with AIC bone graft. Although the length of hospitalization was shorter in the QLB group, it was not statistically significant.

Gili Dardikman, Natan T. Shaked

Digital holographic microscopy is a thriving imaging modality that attracted considerable research interest in quantitative biological cell imaging due to its ability to not only create excellent label-free contrast, but also supply valuable physical information regarding the density and dimensions of the sample with nanometer-scale axial sensitivity. This technique records the interference pattern between a sample beam and a reference beam, and by digitally processing it, one can reconstruct the optical path delay between these beams. Per each spatial point, the optical path delay map is proportional to the product of the sample physical thickness and the integral refractive index of the sample. Since the refractive index of the cell indicates its contents without the need for labeling, it is highly beneficial to decouple cell physical thickness from its refractive index profile. This manuscript reviews various approaches of extracting the refractive index from digital holographic microscopy measurements of cells. As soon as the refractive index of the cell is available, it can be used for either biological assays or medical diagnosis, as reviewed in this manuscript.

Giuseppe Mangioni, Giuseppe Jurman, Manlio De Domenico

A variety of complex systems exhibit different types of relationships simultaneously that can be modeled by multiplex networks. A typical problem is to determine the community structure of such systems that, in general, depend on one or more parameters to be tuned. In this study we propose one measure, grounded on information theory, to find the optimal value of the relax rate characterizing Multiplex Infomap, the generalization of the Infomap algorithm to the realm of multilayer networks. We evaluate our methodology on synthetic networks, to show that the most representative community structure can be reliably identified when the most appropriate relax rate is used. Capitalizing on these results, we use this measure to identify the most reliable meso-scale functional organization in the human protein-protein interaction multiplex network and compare the observed clusters against a collection of independently annotated gene sets from the Molecular Signatures Database (MSigDB). Our analysis reveals that modules obtained with the optimal value of the relax rate are biologically significant and, remarkably, with higher functional content than the ones obtained from the aggregate representation of the human proteome. Our framework allows us to characterize the meso-scale structure of those multilayer systems whose layers are not explicitly interconnected each other -- as in the case of edge-colored models -- the ones describing most biological networks, from proteomes to connectomes.

Denis S. Grebenkov, Ralf Metzler, Gleb Oshanin

The first-passage time (FPT), i.e., the moment when a stochastic process reaches a given threshold value for the first time, is a fundamental mathematical concept with immediate applications. In particular, it quantifies the statistics of instances when biomolecules in a biological cell reach their specific binding sites and trigger cellular regulation. Typically, the first-passage properties are given in terms of mean first-passage times. However, modern experiments now monitor single-molecular binding-processes in living cells and thus provide access to the full statistics of the underlying first-passage events, in particular, inherent cell-to-cell fluctuations. We here present a robust explicit approach for obtaining the distribution of FPTs to a small partially-reactive target in cylindrical-annulus domains, which represent typical bacterial and neuronal cell shapes. We investigate various asymptotic behaviours of this FPT distribution and show that it typically is very broad in many biological situations: thus, the mean FPT can differ from the most probable FPT by orders of magnitude. The most probable FPT is shown to strongly depend only on the starting position within the geometry and to be almost independent of the target size and reactivity. These findings demonstrate the dramatic relevance of knowing the full distribution of FPTs and thus open new perspectives for a more reliable description of many intracellular processes initiated by the arrival of one or few biomolecules to a small, spatially localised region inside the cell.